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  • American Association for Cancer Research (AACR)  (26)
  • Cardnell, Robert J.  (26)
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  • American Association for Cancer Research (AACR)  (26)
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  • 1
    Online Resource
    Online Resource
    Abstract 6206: Combined inhibition of AXL and ATR enhances replication stress, cell death and immune response in small cell lung cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6206-6206
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 6206-6206
    Abstract: Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung tumor. Despite high initial responses to frontline chemo-immunotherapy, therapeutic resistance develops rapidly. There are limited treatment options in the relapsed setting, where the prognosis remains dismal. SCLC tumors experience continuous and high levels of replication stress (RS) due to ubiquitous loss of key cell cycle checkpoints, RB1 and TP53. Frequent amplification and high expression of the transcription factor cMYC further contribute to increased RS. Thus, high levels of RS expose a potential SCLC vulnerability and provide a therapeutic opportunity. Our group and others have shown that AXL, a TAM family receptor tyrosine kinase that is highly expressed in mesenchymal tumors, mediates resistance to chemotherapy, radiation and targeted therapies in SCLC, non-small cell lung cancer and other cancers, through its role in driving epithelial to mesenchymal transition (EMT). More recently, a novel role for AXL in DNA damage repair and tolerance has emerged. Therefore, we hypothesize that AXL targeting may be a potential therapeutic approach in SCLC. We first investigated the transcriptomic expression profile of AXL in SCLC clinical cohorts. AXL-high tumors were seen in a subset of treatment-naïve SCLC tumors, frequently among, but not limited to, the inflamed SCLC subtype. AXL expression was also seen in many relapsed SCLC tumors. As expected, tumors with high AXL expression also expressed several mesenchymal genes and higher EMT scores. Interestingly, among the treatment-naïve SCLC tumors, AXL expression was inversely correlated with a RS signature (rho=-0.54, p & lt;0.001). Next, we tested the effects of AXL inhibition in SCLC in vitro and in vivo models. In a panel of 30 SCLC cell lines, bemcentinib, a selective AXL inhibitor in clinical trials for various advanced solid tumors, exhibited a range of antiproliferative activity, with IC50 values ranging from 41 nM to 10 µM (median IC50 3.1 µM). Bemcentinib also significantly delayed tumor growth in in vivo SCLC models. Biomarkers associated with sensitivity to bemcentinib in SCLC cell lines included markers of RS (cMYC, replication stress score) and DNA damage response (phospho CHK1S345, phospho CHK2T68). Bemcentinib also induced RS, indicated by the activation of ATR/CHK1-mediated RS response pathway, and DNA damage, and the combination with an ATR inhibitor (ceralasertib) showed a greater than additive effect. In a syngeneic model of SCLC, the combination of bemcentinib, ceralasertib and an anti-PDL1 antibody induced significant tumor regression. Together, these promising findings demonstrate that AXL inhibition may be an effective strategy to target the RS vulnerability common in SCLC. Citation Format: Kavya Ramkumar, C. Allison Stewart, Azusa Tanimoto, Qi Wang, Yuanxin Xi, Benjamin B. Morris, Runsheng Wang, Li Shen, Robert J. Cardnell, Jing Wang, Carl M. Gay, Lauren A. Byers. Combined inhibition of AXL and ATR enhances replication stress, cell death and immune response in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6206.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-6206
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 2
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    Abstract CT218: A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT218-CT218
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT218-CT218
    Abstract: Objectives: Small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas (NECs) share many clinical features, including limited response to immune checkpoint inhibitors (ICIs). However, preclinical data suggest synergistic response with combined ICI and poly (ADP-ribose) polymerase inhibitors (PARPi) in SCLC models. This single-institution, phase II trial (NCT04701307) assessed the efficacy of a combination of the anti-PD-1 monoclonal antibody, dostarlimab, with the selective PARPi, niraparib, in patients with relapsed SCLC or NECs. Methods: Eligible patients with SCLC (Cohort 1) or NECs (Cohort 2) had received at least one prior line of therapy and were treated with niraparib 300 mg (or 200 mg if & lt;77kg or platelets & lt; 150,000/µL) PO daily, and dostarlimab 500 mg IV q21d (1000mg IV q42d starting with Cycle 5). Co-primary endpoints were objective response rate (ORR) by RECISTv1.1 and 6-month progression free-survival (PFS6). Using a Bayesian Optimal Phase 2 (BOP2) design, interim futility analyses were planned after enrolling up to 15 SCLC and 9 NEC patients (NEC), respectively. Adverse events (AE) were monitored continuously. Patients underwent biopsies, if feasible, at Cycle 1 and Cycle 3, as well as longitudinal plasma collection for translational studies. Results: From Feb 2021 to Aug 2021, 14 and 9 patients enrolled with SCLC and NEC, respectively. NECs included tumors from gynecological, head/neck, and gastrointestinal sites. In Cohort 1 (SCLC), 12 of 14 patients were evaluable by RECISTv1.1, including 1 complete response (CR), while 4 patients not achieving partial response (PR) had minor responses (-2%, -14%, -19%, and -24% from baseline). Only 1 patient in this cohort achieved PFS6, though 2 additional patients progressed between 5 and 6 months. In Cohort 2 (NEC), 6 of 9 patients were evaluable by RECISTv1.1 and no CR/PRs were observed. One patient did experience durable minor response (-21%), but no patients achieved PFS6. Dose-limiting, niraparib-related hematological AEs, typically thrombocytopenia, occurred in 12 of 23 patients. Non-hematological, treatment-related serious AEs occurred in only 1 patient (Grade 3 inflammatory arthritis), while 1 additional patient experienced brief dose-interruption due to Grade 2 pneumonitis. Preliminary translational data, including bulk and single-cell RNAseq, indicate molecular features, such as transcriptional subtype, are shared across SCLC and NECs and may predict response to this combination. Conclusions: In heavily pre-treated patients across SCLC and NEC cohorts, combined niraparib and dostarlimab failed to exceed interim futility criteria. However, multiple SCLC patients experienced durable disease control, including one patient with sustained CR and associated translational studies point to potential biomarker-driven approaches in the future. Trial supported by GlaxoSmithKline. Citation Format: Carl M. Gay, C. Allison Stewart, Michael Frumovitz, Junya Fujimoto, Yuann xi, Qi Wang, Runsheng Wang, Veronica Novegil, Mehmet Altan, Tina Cascone, Arvind Dasari, Yasir Y. Elamin, Frank V. Fossella, Bonnie S. Glisson, Charles S. Lu, Marcelo V. Negrao, Ferdinandos Skoulidis, Natalie Vokes, Robert J. Cardnell, Ignacio I. Wistuba, Jing Wang, John V. Heymach, Lauren A. Byers. A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT218.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT218
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 3
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    AXL Inhibition Induces DNA Damage and Replication Stress in Non–Small Cell Lung Cancer Cells and Promotes Sensitivity to ATR Inhibitors
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Research Vol. 19, No. 3 ( 2021-03-01), p. 485-497
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 3 ( 2021-03-01), p. 485-497
    Abstract: AXL, a TAM (TYRO3, AXL, and MERTK) family receptor tyrosine kinase, is increasingly being recognized as a key determinant of resistance to targeted therapies, as well as chemotherapy and radiation in non–small cell lung cancer (NSCLC) and other cancers. We further show here that high levels of AXL and epithelial-to-mesenchymal transition were frequently expressed in subsets of both treatment-naïve and treatment-relapsed NSCLC. Previously, we and others have demonstrated a role for AXL in mediating DNA damage response (DDR), as well as resistance to inhibition of WEE1, a replication stress response kinase. Here, we show that BGB324 (bemcentinib), a selective small-molecule AXL inhibitor, caused DNA damage and induced replication stress, indicated by ATR/CHK1 phosphorylation, more significantly in TP53-deficient NSCLC cell lines. Similar effects were also observed in large-cell neuroendocrine carcinoma (LCNEC) cell lines. High AXL protein levels were also associated with resistance to ATR inhibition. Combined inhibition of AXL and ATR significantly decreased cell proliferation of NSCLC and LCNEC cell lines. Mechanistically, combined inhibition of AXL and ATR significantly increased RPA32 hyperphosphorylation and DNA double-strand breaks and induced markers of mitotic catastrophe. Notably, NSCLC cell lines with low levels of SLFN11, a known predictive biomarker for platinum and PARP inhibitor sensitivity, were more sensitive to AXL/ATR cotargeting. These findings demonstrate a novel and unexpected role for AXL in replication stress tolerance, with potential therapeutic implications. Implications: These findings demonstrate that the combination of AXL and ATR inhibitors could be a promising therapeutic combination for NSCLC, LCNEC, and other cancers.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-20-0414
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 4
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    Abstract 3854: TNIK inhibition as a novel therapeutic in cMyc high/TTF1 low SCLC
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3854-3854
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 3854-3854
    Abstract: Background: Small cell lung cancer (SCLC) is a highly lethal malignancy, with rapidly acquired chemotherapy resistance. Some studies have reported that Wnt signaling pathway activation promoted cell proliferation and was correlated with chemo-resistance in SCLC. None of the therapies targeting Wnt pathway components of the transmembrane and the cytoplasm have been successful in a clinical application due to toxicity and insufficient efficacy. However, targeting Wnt signaling inside the nucleus has been drawing increasing attention as cancer therapeutics. TRAF2 and NCK-interacting protein kinase (TNIK), which interacts with downstream effectors, TCF4/β-catenin transcriptional complex, is an essential activator of Wnt target genes. TNIK is highly expressed in several cancers for cell proliferation, thus TNIK is expected as a novel druggable target. On the other hand, the question remains whether TNIK is a critical target in SCLC. We hypothesize that a TNIK inhibitor has potent anti-tumor effects in SCLC and its promising biomarkers exist. Methods: We used 29 SCLC cell lines including all four subtypes defined by differential expression of transcription factors ASCL1, NEUROD1, POU2F3, and inflamed gene signature (SCLC-A, N, P, and I, respectively) to evaluate the effect of a TNIK inhibitor, NCB-0846 in vitro. We correlated NCB-0846 IC50 values with proteomic profiling (Reverse Phase Protein Array, RPPA) data. Protein expression was examined by western blotting. Results: NCB-0846 markedly reduced cell proliferation in SCLC-N and P cell lines. There was a strong positive correlation between cMyc and the efficacy of NCB-0846 (r=-0.484, P & lt;0.01), while a negative correlation between TTF1 and the efficacy (r=0.569, P & lt;0.01). Additionally, NCB0846 decreased the expression of cMyc in cMyc-high/TTF-1 low SCLC cells. Conclusions: These findings indicate that TNIK inhibitors may be a new personalized molecular-targeted therapy in cMyc-high/TTF-1-low SCLC. Citation Format: Azusa Tanimoto, Robert J. Cardnell, Benjamin B. Morris, Kavya Ramkumar, Shen Li, Qi Wang, Allison C. Stewart, Carl Michael Gay, Jing Wang, Lauren Averett Byers. TNIK inhibition as a novel therapeutic in cMyc high/TTF1 low SCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3854.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-3854
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract 232: Comprehensive metabolic profiling and vulnerabilities to metabolic inhibitors among small cell lung cancer subtypes
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 232-232
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 232-232
    Abstract: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor that constitutes approximately 14% of all lung cancers diagnosed in the United States. Despite recent advances in treatment options, recurrence is a major challenge and long-term survival remains poor underscoring the importance of investigating mechanisms of treatment resistance and therapeutic strategies. Interestingly, our laboratory has recently uncovered evidence for the classification of SCLC into distinct subtypes, each with unique gene expression patterns and therapeutic vulnerabilities. These subtypes are characterized by differential expression of the transcription factors ASCL1, NEUROD1, or POU2F3. A fourth subtype is negative for all three transcription factors and has prominent expression of immune genes, thus is termed the Inflamed subtype. These subtypes are associated with differences in drug sensitivity, biomarker signatures, and mechanisms of cellular growth. One facet of tumor biology that has not been explored across the subtypes, or in SCLC in general, is the metabolic mechanisms of energy generation. Although metabolic reprogramming from mitochondrial respiration to glycolysis is considered a major hallmark of cancer, increasing evidence suggests that mitochondrial or amino acid dependencies may also contribute to treatment resistance. Therefore, understanding the metabolic demand, particularly among the subtypes, is critical for the development of new therapies. To address this, gene set enrichment analysis was applied to 81 human SCLC tumors categorized by subtype, and revealed differential gene expression correlating to pathways such as fatty acid metabolism in POU2F3 and reactive oxygen species in Inflamed that was confirmed by reverse phase protein analysis (RPPA). Further, we evaluated nutrient requirements, glycolysis dependence, and mitochondrial function in human SCLC cell lines and found differences in glucose uptake and subsequent lactate generation between the subtypes suggesting that glycolysis inhibition may be effective in particular subsets. Based on this, we then tested the efficacy of PFK-158 (glycolysis inhibitor) on cellular proliferation and metabolic function in these cell lines, which revealed variations in susceptibility dependent on subtype classification. Together, this data serves to enhance the current understanding of SCLC mechanisms of growth and provides evidence for metabolic inhibition as a potential therapeutic opportunity. Citation Format: Kasey R. Cargill, Carl M. Gay, Robert J. Cardnell, You-Hong Fan, Qi Wang, Lixia Diao, Jing Wang, Lauren A. Byers. Comprehensive metabolic profiling and vulnerabilities to metabolic inhibitors among small cell lung cancer subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 232.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-232
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
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    Abstract 2335: Targeting MYC-enhanced glycolysis in small cell lung cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2335-2335
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2335-2335
    Abstract: Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancer cases with a poor five year survival rate of 6%. The National Cancer Institute has designated SCLC as one of two “recalcitrant” cancers and urges translational research to advance treatment options. In our effort to maximize treatment benefits, we have aimed our investigation at uncovering metabolic differences contributing to disease progression that may be targeted through specific pathway inhibition. Although metabolism is relatively unstudied in SCLC, metabolic reprogramming is recognized as a hallmark of cancer and can be regulated by several different mechanisms. Notably, the transcription factor MYC is overexpressed in 30% SCLC tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. While mitochondrial respiration is the preferred source of energy production in terminally differentiated cells, many cancer cells switch to become predominantly glycolytic in an effort to generate energy quickly and produce biomolecules and electron carriers required for proliferation—a phenomena known as the Warburg Effect. Since MYC is expressed in only a subset of highly aggressive SCLC, we applied bimodal separation to both patient and cell line SCLC datasets to establish defined MYC subsets (MYCLow; MYCHigh) and performed gene ontology pathway analysis to genes that were significantly upregulated among the MYC-expressing samples. This revealed that 37% of significantly upregulated genes were linked to metabolic processes and further investigation showed many of those genes were linked to the glycolysis pathway. We also confirmed upregulation of protein expression through reverse phase protein array (RPPA). With glycolysis proving to be increased in MYCHigh samples, we simultaneously characterized pathway utilization in cell lines at baseline and in the presence of a potent glycolysis inhibitor. MYCHigh cell lines exhibited greater glucose consumption and lactate secretion, which was significantly decreased by glycolytic inhibition. Likewise, mitochondrial analysis revealed lower oxygen consumption and ATP production that were further reduced in the presence of the glycolysis inhibitor. Although mitochondrial density was unchanged regardless of MYC expression or glycolytic inhibition, reactive oxygen species (ROS) generation was greatly enhanced in the MYCHigh subset upon suppression of glycolysis. Lastly, SCLC xenografts derived from a MYCHigh SCLC cell line showed significantly slower tumor growth whereas MYCLow derived xenografts exhibited no significant difference in tumor growth. Together, these data provide evidence of metabolic differences among SCLC subsets such that MYC expression induces reliance on glycolysis, which can be targeted for therapeutic intervention. Citation Format: Kasey R. Cargill, C. Allison Stewart, Elizabeth M. Park, Robert J. Cardnell, You Hong Fan, Qi Wang, Lixia Diao, Wai Kin Chan, Philip L. Lorenzi, Jing Wang, Lauren A. Byers. Targeting MYC-enhanced glycolysis in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2335.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2335
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract P079: The impact of BCL2 expression on sensitivity to the novel Aurora kinase B inhibitor AZD2811 in small cell lung cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Molecular Cancer Therapeutics Vol. 20, No. 12_Supplement ( 2021-12-01), p. P079-P079
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 20, No. 12_Supplement ( 2021-12-01), p. P079-P079
    Abstract: Purpose: Small cell lung cancer (SCLC) is a highly lethal malignancy, with rapidly-acquired therapeutic resistance. In contrast to non-SCLC, treatment strategies based on molecular subtypes have not been well established. Aurora kinase family proteins (AURKA and AURKB) are essential for cell division, regulating chromosomal segregation during mitosis, and are upregulated in cancer. Our group has demonstrated that cMYC-driven SCLC tumors were susceptible to an AURKA inhibitor, alisertib, making AURK proteins an attractive targeted therapeutic approach. A novel AURKB inhibitor, AZD2811NP (nanoparticle), is now being investigated in relapsed SCLC patients (NCT02579226), but molecular mechanisms of resistance have not yet been identified. Here, we hypothesize that targeting predictive markers related to the effect of AZD2811 may reinforce susceptibility to AURKB inhibition. Experimental Design: We evaluated susceptibility to AZD2811 in 63 human-derived SCLC cell lines using 96-hour proliferation assays. To identify translatable biomarkers of response, we correlated AZD2811 IC50 values with genomic (whole exome sequencing, WES), transcriptomic (RNASeq), and proteomic profiling (Reverse Phase Protein Array, RPPA) data. We validated changes in apoptosis and DNA damage markers induced by AZD2811 in SCLC cells infected with the lentivirus vectors expressing BCL-2 and shRNA against BCL-2 using western blot. We used SCLC patient-derived xenograft (PDX) models with distinct BCL-2 profiles to evaluate in vivo antitumor effect. Results: In the SCLC cells treated with AZD2811, 15/63 (24%) and 10/63 (16%) cell lines showed high sensitivity (IC50 & lt;30 nM, Cmax) and intermediate sensitivity (IC50=30-100nM). Comparing protein expression, we found that cMYC (Fold change, FC:2.5; P = 0.015) were a positive biomarker of sensitivity, while high BCL-2 (FC:1.86; P = 0.032) associated with resistance. cMYC-high SCLC cell lines that were susceptible to AZD2811 became resistant when BCL-2 was overexpressed. Conversely, BCL-2 knock-down enhanced response to AZD2811, inducing apoptosis and DNA damage, in BCL-2-high cells that were originally resistant to single-agent AZD2811. Similar to Bcl-2 knock-down, treatment with venetoclax (a BCL-2 inhibitor routinely used in other cancers) enhanced apoptosis and DNA damage induction in combination with AZD2811 in cells overexpressing BCL-2. In PDX models with high BCL-2, combination of AZD2811 and venetoclax prominently induced tumor regression and apoptosis compared with each monotherapy, while there was no significant difference in PDX models with low BCL-2 between the combination and the monotherapy. Conclusions: Our preclinical results indicate that high BCL-2 expression reduced the efficacy of AZD2811 in SCLC models, but that Bcl2-driven resistance could be overcome with the combined use of BCL-2 and AURKB inhibitors. Findings support a promising rational combination therapy for BCL-2-high SCLC to enhance response to aurora kinase B inhibition. Citation Format: Azusa Tanimoto, Carminia M. Della Corte, Kavya Ramkumar, Robert J. Cardnell, Allison C. Stewart, Carl M. Gay, Lauren Averett Byers, Qi Wang, Li Shen, Jing Wang, Jon Travers. The impact of BCL2 expression on sensitivity to the novel Aurora kinase B inhibitor AZD2811 in small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P079.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-21-P079
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 8
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    Abstract 2602: Combined inhibition of AXL and ATR enhances cell death and immune response in small cell lung cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2602-2602
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2602-2602
    Abstract: Small cell lung cancer (SCLC) is an aggressive lung tumor of neuroendocrine origin with a dismal 5-year survival rate. Despite high response rates to initial therapy, rapid development of therapeutic resistance limits overall survival. There are also limited treatment options, particularly in the relapsed setting. Our group and others have shown that AXL, a TAM family receptor tyrosine kinase that is highly expressed in mesenchymal tumors, mediates resistance to chemotherapy, radiation and targeted therapies in SCLC, non-small cell lung cancer and other cancers, through its roles in driving epithelial to mesenchymal transition and DNA damage repair. AXL has also been implicated in immune escape. Based on these findings, we hypothesize that AXL targeting may be a potential therapeutic approach in SCLC. We screened BGB324 (bemcentinib), a selective small-molecule AXL inhibitor in clinical trials for various advanced solid tumors, in a panel of 60 human SCLC cell lines using cell viability assays. The SCLC cell lines showed a range of sensitivities, with IC50 values ranging from 41 nM to 10 µM (median IC50 3.1 µM) with NeuroD1-driven SCLC cell lines being highly sensitive to BGB324 (ANOVA p & lt;0.05). BGB324 also showed potent inhibition of tumor growth in an in vivo SCLC model. BGB324 further combined synergistically with an ATR inhibitor (AZD3738) and induces significant DNA damage. In a syngeneic model of SCLC, the combination of BGB324, AZD6738 and an anti-PDL1 antibody combination also induced significant tumor regression. Together, these promising findings show that AXL inhibition may be effective in SCLC and support further investigation of AXL and ATR inhibitor combinations with immune checkpoint blockade. Citation Format: Kavya Ramkumar, Azusa Tanimoto, C. Allison Stewart, Qi Wang, Li Shen, Robert J. Cardnell, B. Leticia Rodriguez, Don L. Gibbons, Jing Wang, Carl M. Gay, Lauren A. Byers. Combined inhibition of AXL and ATR enhances cell death and immune response in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2602.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-2602
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Clinical Cancer Research Vol. 29, No. 16 ( 2023-08-15), p. 3237-3249
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 29, No. 16 ( 2023-08-15), p. 3237-3249
    Abstract: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. Experimental Design: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. Results: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor. Conclusions: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-23-0375
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 2036787-9
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    Abstract B15: The oral Chk1 inhibitor, SRA737, synergizes with immune checkpoint blockade in small-cell lung cancer (SCLC)
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Immunology Research Vol. 8, No. 4_Supplement ( 2020-04-01), p. B15-B15
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    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 8, No. 4_Supplement ( 2020-04-01), p. B15-B15
    Abstract: Background: Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer. Despite the recent success of immunotherapy in other indications, only a minority of SCLC patients respond to immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) either as a monotherapy or combination. Therefore, there is a strong need to develop strategies to enhance the efficacy of immunotherapy in SCLC. Our group previously discovered that SCLC exhibits high expression of checkpoint kinase 1 (Chk1) and showed that preclinical in vivo models of SCLC respond to Chk1 inhibition. Based on data from others and our group, we hypothesized that targeting Chk1 can enhance antitumor immunity and synergize with ICB. Results: SRA737 treatment decreased cell viability with a range of potencies in a panel of SCLC cell lines in vitro. This was accompanied by an induction of double-strand breaks in sensitive cell lines as demonstrated by increased γ-H2AX. Intriguingly, SRA737 also led to an increase in micronuclei formation and STING activation in cells in vitro. Cell surface and total PD-L1 protein were increased following SRA737 treatment in vitro, further supporting a potential benefit of combining the drug with immune checkpoint blockade therapy in vivo. As hypothesized, SRA737 showed strong synergy with anti-PD-L1 antibody in an immunocompetent xenograft SCLC model. Triple-knockout SCLC cells generated from a GEMM mouse model with conditional deletion of Trp53, Rb1 and p130 were implanted into the flank of B6129F1 mice. The mice were treated for three weeks with either IgG (control), SRA737 (100mg/kg, either 3/7 or 5/7 days), anti-PD-L1 (300ug, 1/7 days) or the combination. While anti-PD1 antibody treatment was largely ineffective, SRA737 significantly delayed tumor growth (at Day 21: T/C=0.30 for 3/7 days and T/C=0.28 for 5/7 days). Combination treatment with SRA737 and anti-PD-L1 demonstrated remarkable antitumor efficacy, resulting in stable disease following SRA737 schedule of 3/7 days (T/C=0.12) and tumor regressions following SRA737 schedule of 5/7 days (T/C=0.1). These effects were sustained after treatment cessation and the long-term survival benefit is being assessed. Discussion: The intrinsic antitumor activity of the Chk1 inhibitor, SRA737, was significantly enhanced by addition of an anti-PD-L1 antibody, leading to tumor regressions in an immunocompetent SCLC model. Preliminary evidence suggests SRA737 induces micronuclei formation, STING activation and PD-L1 expression in tumor cells. Further studies to elucidate the mechanism of Chk1 inhibition-induced antitumor immunity in SCLC are ongoing. SRA737 is currently being tested in clinical trials both as a monotherapy and in combination with other agents. Given that the anti-PD-L1 antibody opdivo is now approved for SCLC, our data suggest intriguing possibilities for therapeutic synergy between the oral Chk1 inhibitor, SRA737, and ICB therapy that warrant further clinical investigation. Citation Format: Triparna Sen, Snezana Milutinovic, Robert J. Cardnell, Lixia Diao, Youhong Fan, Ryan J. Hansen, Bryan Strouse, Michael P. Hedrick, Christian Hassig, Jing Wang, Lauren A. Byers. The oral Chk1 inhibitor, SRA737, synergizes with immune checkpoint blockade in small-cell lung cancer (SCLC) [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B15.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM18-B15
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2732517-9
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