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  • American Association for Cancer Research (AACR)  (13)
  • Tang, Ximing  (13)
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  • American Association for Cancer Research (AACR)  (13)
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  • 1
    Online Resource
    Online Resource
    Abstract 955: Specific forms of mutant KRAS predict patient benefit from targeted therapy in the BATTLE-1 clinical trial in advanced non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 955-955
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 955-955
    Abstract: Mutant KRAS (mut-KRAS) is present in 17-25% of all human cancers, where it plays a critical role in driving cancer cell growth and resistance to therapy. Despite numerous attempts, there is still no effective therapy for mut-KRAS tumors. Understanding the signaling mechanisms activated by mut-KRAS and finding agents to inhibit mut-KRAS signaling are important unmet needs in cancer therapy today. The recently completed BATTLE-1 clinical trial, a prospective, multi-arm, biopsy-mandated, biomarker-driven, clinical trial in advanced refractory non-small cell lung cancer (NSCLC), found that mut-KRAS did not accurately predict patient outcome (progression-free survival) to targeted intervention. This finding contradicted published evidence for such a relationship from colon cancer and some previous NSCLC studies. We explored more specifically the nature of the KRAS mutations, which are primarily found at codons 12 and 13, where different base substitutions lead to alternate amino acid (aa) substitutions. NSCLC has a much higher proportion of mut-KRAS G12C(cysteine) aa substitutions (47%) due to carcinogens in tobacco smoke, and only 15% mut-KRAS have G12D(aspartate). These data contrast those in other solid tumors, such as colon or pancreas, which predominantly manifest mut-KRAS G12D (50%) and only 9% mut-KRAS G12C. In a subset analysis of the BATTLE-1 data, we showed significantly worse progression-free survival in patients with mut-KRAS G12C, versus other mut-KRAS including G12D (p=.041) and who were treated with erlotinib, vandetanib or sorafenib. In a panel of NSCLC cell lines with known mut-KRAS aa substitutions to identify pathways activated by the different mut-KRAS genotypes, we found that mut-KRAS G12D activates both PI-3-K and MEK signaling, while mut-KRAS G12C does not and alternatively activates PKCζ and RAL signaling. This finding was confirmed in immortalized human bronchial epithelial (HBEC) cells stably transfected with wt-KRAS or different forms of mut-KRAS. Our molecular modeling studies show that the different conformation imposed by mut-KRAS G12C could lead to altered association with downstream signaling transducers, compared to mut-KRAS G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRAS may be addictive; and that different combinations of inhibitors of downstream signaling may be needed for different mut-KRAS. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 955. doi:10.1158/1538-7445.AM2011-955
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-955
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
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    Comprehensive Biomarker Analysis and Final Efficacy Results of Sorafenib in the BATTLE Trial
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 24 ( 2013-12-15), p. 6967-6975
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 24 ( 2013-12-15), p. 6967-6975
    Abstract: Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program. Patients and Methods: Patients with previously treated non–small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS). Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04–3.58] and 8.48 months (95% CI, 5.78–10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-κB, and hypoxia pathways were identified potential drivers of sorafenib resistance. Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials. Clin Cancer Res; 19(24); 6967–75. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-1818
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 3
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    Abstract LB-88: Gene expression signatures predictive of clinical outcome and tumor mutations in refractory NSCLC patients (pts) in the BATTLE trial (Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination)
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-88-LB-88
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. LB-88-LB-88
    Abstract: Background: There are currently no established markers to identify pts bearing wild-type EGFR who are likely to benefit from erlotinib (ERLO). The EGFR and Kras pathways, and epithelial to mesenchymal transition (EMT), have been associated with response/resistance to EGFR inhibitors. We developed gene signatures for these pathways and tested whether they were predictive of disease control (DC) and tumor mutations using gene expression profiles from pts in the BATTLE trial, and developed novel markers for ERLO benefit in wt EGFR pts. Methods: Gene expression profiles (Affymetrix HG1.0ST) from pretreatment core needle biopsies (CNBs) were obtained from 101 BATTLE pts. Pathways signatures were developed using independent datasets from resected NSCLC pts and cell lines. A robust EGFR mutation signature was derived by comparing genes differentially expressed in mutated and wt EGFR lung adenocarcinoma from 3 independent institutions, and validated in three independent sets, both in vivo and in vitro. A KRAS signature was similarly derived. An EMT signature was derived by identifying genes with a bimodal distribution and correlated with known EMT genes (E-cadherin, vimentin, N-cadherin, FN-1) using 54 NSCLC cell lines, and validated in an independent panel of HN cell lines and across different platforms. A novel 5-gene signature was derived using erlotinib-treated BATTLE patients with or without 8 week DC, the primary study endpoint. Results: The EGFR and Kras signatures predicted EGFR and Kras mutations, respectively, in BATTLE patients (AUC 0.72 by ROC analysis, p=0.03 for EGFR; AUC 0.67, p=0.0.01 for KRas signature). In pts with wt EGFR and Kras, the EMT and 5-gene, but not the EGFR or KRas signatures, were associated with improved DC in ERLO treated pts (EMT signature: 64% for epithelial vs 10% mesenchymal groups, p=0.02; 5-gene: 83% vs 0%, p= & lt;.001) and progression-free survival (PFS). The EGFR, EMT and 5-gene signatures were also significantly associated with in vitro sensitivity to ERLO in NSCLC cell lines. LCN2/NGAL, part of the 5-gene signature, was found to be associated with the epithelial phenotype. Potential therapeutic targets associated with mesenchymal phenotype including Axl were identified by the EMT signature. Conclusions: Gene expression profiling from CNBs is a feasible approach for predicting response and identifying activated oncogenic pathways and potential therapeutic targets in refractory NSCLC pts. EGFR and Kras signatures predicted mutation status but, in wt EGFR patients, did not predict efficacy. EMT and a novel 5-gene signature including LCN2/NGAL were predictive of DC in pts with wt EGFR treated in BATTLE and merit further investigation as markers of benefit for EGFR inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-88. doi:10.1158/1538-7445.AM2011-LB-88
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-LB-88
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 4
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    Increased VEGFR-2 Gene Copy Is Associated with Chemoresistance and Shorter Survival in Patients with Non–Small-Cell Lung Carcinoma Who Receive Adjuvant Chemotherapy
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 16 ( 2011-08-15), p. 5512-5521
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 16 ( 2011-08-15), p. 5512-5521
    Abstract: VEGF receptor-2 (VEGFR-2 or kinase insert domain receptor; KDR) is a known endothelial target also expressed in NSCLC tumor cells. We investigated the association between alterations in the KDR gene and clinical outcome in patients with resected non–small-cell lung carcinoma (NSCLC; n = 248). KDR copy number gains (CNG), measured by quantitative PCR and fluorescence in situ hybridization, were detected in 32% of tumors and associated with significantly higher KDR protein and higher microvessel density than tumors without CNGs. KDR CNGs were also associated with significantly increased risk of death (HR = 5.16; P = 0.003) in patients receiving adjuvant platinum-based chemotherapy, but no differences were observed in patients not receiving adjuvant therapy. To investigate potential mechanisms for these associations, we assessed NSCLC cell lines and found that KDR CNGs were significantly associated with in vitro resistance to platinum chemotherapy as well as increased levels of nuclear hypoxia inducible factor-1α (HIF-1α) in both NSCLC tumor specimens and cell lines. Furthermore, KDR knockdown experiments using small interfering RNA reduced platinum resistance, cell migration, and HIF-1α levels in cells bearing KDR CNGs, providing evidence for direct involvement of KDR. No KDR mutations were detected in exons 7, 11, and 21 by PCR-based sequencing; however, two variant single nucleotide polymorphism genotypes were associated with favorable overall survival in adenocarcinoma patients. Our findings suggest that tumor cell KDR CNGs may promote a more malignant phenotype including increased chemoresistance, angiogenesis, and HIF-1α levels, and that KDR CNGs may be a useful biomarker for identifying patients at high risk for recurrence after adjuvant therapy, a group that may benefit from VEGFR-2 blockade. Cancer Res; 71(16); 5512–21. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-2614
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 5
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    Abstract 4819: Gene-expression profiles predict sorafenib efficacy in wild-type EGFR non-small cell lung cancer (NSCLC)
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4819-4819
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 4819-4819
    Abstract: Background: Results from our Biomarkers-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) program suggest that patients with chemorefractory wild-type (wt) EGFR NSCLC including those with mutant KRAS may benefit from sorafenib. Using 3 different approaches, we tested the hypothesis that gene expression profiles from wild-type (wt) EGFR tumors may predict sorafenib efficacy by capturing effects on multiple targets. Material and Methods: Baseline tumor biopsies from 37 BATTLE patients (pts) with EGFR wt tumors and treated with sorafenib were profiled (Affymetrix Human Gene 1.ST), as well as 68 EGFR wt NSCLC cell lines with available IC50 to sorafenib (Illumina HumanWG-6 v3.0 expression beadchip). (i) We first developed an In vitro Sorafenib Signature (ISS). Correlation of IC50 with each individual probe expression level was computed. Most significant probes were summarized by the first principal component (PC), and correlated with IC50 of sorafenib. To validate the signature, the first PC was computed in BATTLE samples, and progression-free survival (PFS) of pts with high- vs. low-sensitivity signature was compared based on the median of the first PC. (ii) Alternatively, we developed a Clinical Sorafenib Signature (CSS) using BATTLE samples. We compared 23 (62%) pts who achieved 8-week disease control with 14 (38%) who did not (t-test). Most significant probesets were summarized by the first PC and PFS of pts with a high- vs. low-sensitivity signature were compared. To validate the signature, the first PC was computed in cell lines and correlated with IC50 of sorafenib. (iii) Finally, we tested a previously reported KRAS mutation gene expression signature derived by comparing genes differentially expressed in mutant vs. wt KRAS early stage resected lung adenocarcinomas, in 124 BATTLE samples including 24 mutant KRAS. Results: (i) The ISS included 50 probes. The first PC was correlated with the IC50 of sorafenib (rho = –0.71, P & lt; 0.0001). The ISS was then tested in BATTLE and PFS was significantly different in pts with the high- (median PFS 3.61 months) vs. the low-sensitivity signature (median PFS 1.84 months, log-rank P = 0.0263). (ii) The CSS developed in BATTLE included 80 probesets summarized using the first PC. PFS was significantly different in pts with the high- vs. the low-sensitivity signature (log-rank P & lt; 0.0001). The CSS was then tested in cell lines and the first PC was signicantly correlated with IC50 of sorafenib (rho = 0.24, P = 0.0483). (iii) Finally, the KRAS signature was significantly associated with KRAS mutation, but no association was observed with outcome in pts treated with sorafenib in BATTLE. Conclusion: We report 2 gene expression signatures, ISS and CSS, that predicted benefit from sorafenib in patients with chemorefractory NSCLC and in vitro sensitivity to sorafenib respectively. Further validation is planned in our ongoing BATTLE-2 program. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4819. doi:1538-7445.AM2012-4819
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-4819
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 6
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    The BATTLE Trial: Personalizing Therapy for Lung Cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Discovery Vol. 1, No. 1 ( 2011-06-01), p. 44-53
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 1, No. 1 ( 2011-06-01), p. 44-53
    Abstract: The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non–small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. (ClinicalTrials.gov numbers: NCT00409968, NCT00411671, NCT00411632, NCT00410059, and NCT00410189.) Significance: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with “real-time” biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment. Cancer Discovery; 1(1); 44–53. © 2011 AACR. Read the Commentary on this article by Sequist et al., p. 14 Read the Commentary on this article by Rubin et al., p. 17 This article is highlighted in the In This Issue feature, p. 4
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8274.CD-10-0010
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    Abstract 787: Differences in protein expression patterns in lung adenocarcinomas arising in never versus ever smokers
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 787-787
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 787-787
    Abstract: Background. Approximately 25% of lung cancer cases worldwide, mostly adenocarcinomas, are not attributable to tobacco use. Despite that some striking differences have been identified in the epidemiological, clinical and molecular characteristics of lung cancer arising in never smokers versus smokers, our current knowledge of lung adenocarcinoma in never smokers is still limited. Methods. We examined the immunohistohemical (IHC) expression of 101 proteins in surgically resected lung adenocarcinoma tissue microarray specimens obtained from 52 never smokers and compared the findings with 152 tumors obtained from ever smokers. The markers examined included a wide variety of tumor-related proteins, representing all hallmarks of cancer (Hanahan and Weinberg, Cell 2000). The IHC expression was assessed at cytoplasm [c], membrane [m] , and nucleus [n] of malignant cells, and in stromal cells. Univariate and multivariate (adjusting by patients’ sex, and tumor stage and EGFR mutation status) statistical analyses were performed to assess the statistical differences in the expression of markers according to smoking status. The expression of the markers was correlated with patients’ clinical characteristics and tumors’ pathological features and EGFR mutational status. Results. In the multivariate analysis, tumors from smokers showed a relatively high number of markers (n=32) with significant higher expression compared with tumors from never smokers. Interestingly, in the univariate analysis, nine markers showed significantly higher expression in tumors from never smokers compared with ever smokers, including FGFR-1 [n], FGFR-2 [n] , ER-alpha [n], CD44 [c] , FOLR1 [m], IGFBP3 [n] , IL-1alpha [c], NF-kB [n] , survivin [n] and RGS17 [n] . In the multivariate analysis, six markers showed significantly higher expression in tumors from never smokers, including FGFR-2 [n] (P=0.018), CD44 [c] (P=0.001), c-Met [c] (P=0.045) and [m] (P=0.017), E-Cadherin [m] (P=0.003), IGFBP3 [n] (P=0.0009) and p-HER3 [m] (P=0.035). Twenty-nine markers showed significant association with EGFR mutations in tumors in the multivariate analysis adjusting by patients’ sex and smoking status, and tumor stage. Additionally, 47 markers showed significant differences in the level of expression comparing patients’ smoking status, including current, former and never smokers. Conclusion. Our findings indicate that there are multiple molecular differences between lung adenocarcinomas arising in never and ever smokers, suggesting that they are different entities. These findings have implications for the selection of molecular targets for developing novel therapy in patients with lung adenocarcinoma based on their smoking history (Supported by grant VITAL W81XWH-04-1-0142 and UT-Lung SPORE P50CA070907). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 787.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-787
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 8
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    Abstract 3576: Rictor alterations elicit non-canonical signaling mechanisms contributing to tumorigenicity and therapeutic resistance in non-small cell lung cancer (NSCLC)
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3576-3576
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3576-3576
    Abstract: Background: Rictor (RPTOR independent companion of MTOR, complex 2) is a highly conserved protein and is a critical component for proper assembly and functionality of the mTORC2 complex. The goal of our current study is to characterize the functional consequences of genomic alterations of RICTOR in advanced refractory NSCLC. Our preliminary data suggest that Rictor alterations have the potential to not only signal canonically through AKT, but also provide cancer cells with alternate, more advantageous oncogenic signaling via non-canonical mechanisms. Methods: We correlated genomic data (DNA hybrid capture based next generation sequencing (NGS), Foundation Medicine, Inc.), gene expression profiling, and clinical outcome in the context of the ongoing BATTLE-2 clinical trial of targeted therapies in chemo-refractory NSCLC (198 cases). We further (1) surveyed early stage NSCLC (230 cases) in The Cancer Genome Atlas (TCGA) database and performed two-way hierarchical clustering comparing gene expression profiling in amplified vs. diploid cases; (2) utilized a single-nucleotide polymorphism array to select RICTOR amplified and diploid NSCLC cell lines; (3) assessed Rictor protein and RNA expression by Western blot and qRT-PCR, respectively; and (4) performed RICTOR knockdown using siRNA followed by migration, invasion, and clonogenic assays. Results: In the BATTLE-2 cases, we identified 15% of RICTOR alterations (9% amplifications, 6% mutations, mutually exclusive) preferentially associated with resistance to all therapies (AKTi+MEKi, erlotinib+AKTi, sorafenib, or erlotinib). In the TCGA we found: (1) 10% of RICTOR amplifications and 3% mutations; (2) significant correlation between amplification and elevated RICTOR gene expression; and (3) a putative functional gene expression signature associated with RICTOR amplification. In diploid cell lines we found concordance between AKT phosphorylation and activation of other downstream mTORC2 targets (i.e. SGK1 and PKCα), but in RICTOR amplified cell lines we witnessed a discordant activation of these pathways, and thus were able to define unique signaling class systems in our cell lines harboring RICTOR alterations. Furthermore, following RICTOR knockdown in our amplified cell lines, a reduction in clonogenic, migratory, and invasive capacity was seen, suggesting that RICTOR amplification may provide a survival advantage in select cancer cells by tipping the signaling balance toward a non-canonical oncogenic pathway (AKT-independent). Conclusion: Rictor alterations may define a new molecular NSCLC subtype with distinct biology that expose unique avenues for therapeutic intervention. Ongoing studies are underway to explore specific therapeutic strategies, non-canonical signaling and Rictor mutations. Supported by: NHI-NCI CA155196 & 2P50CA070907-16A1 Citation Format: Dennis Ruder, Vassiliki Papadimitrakopoulou, Kazuhiko Shien, Neda Kalhor, J. Jack Lee, Waun K. Hong, Ximing Tang, Luc Girard, John D. Minna, Lixia Diao, Jing Wang, Nana E. Hanson, James Sun, Vincent Miller, Garrett Frampton, Roy S. Herbst, Ignacio I. Wistuba, Julie G. Izzo. Rictor alterations elicit non-canonical signaling mechanisms contributing to tumorigenicity and therapeutic resistance in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3576. doi:10.1158/1538-7445.AM2015-3576
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3576
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    Abstract 745: Oncostatin M receptor activation leads to molecular targeted therapy resistance in non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 745-745
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 745-745
    Abstract: Background: The emergence of molecular targeted therapies against driver mutations and gene fusions has resulted in significant therapeutic advances within a subset of non-small cell lung cancer (NSCLC) patients. However, even when targeted therapy is effective, patients eventually develop resistance and better therapies in this setting are still being sought. Preliminary studies, from the ongoing BATTLE-2 clinical trial in chemo-refractory NSCLC, identified a number of molecular candidates portending to targeted therapy resistance, including the oncostatin M (OSM) and leukemia inhibitory factor (LIF) receptors (OSMR, LIFR), both co-localized on a frequently amplified chromosome 5p region. In this study, we investigated the functional contribution of the OSM pathway to targeted therapy resistance in NSCLC. Materials and Methods: We analyzed OSM, OSMR, LIFR, and associated downstream pathways in a panel of OSMR-LIFR amplified (10) and diploid (10) NSCLC cell lines, in both mono- and co-culture experiments using human normal and lung cancer-associated fibroblasts (CAFs). We assessed the effect of OSM pathway stimulation and blockade on sensitivity to a variety of molecularly targeted agents. Further, we performed correlative studies using the BATTLE-2 molecular dataset. Results: OSM stimulation activated cell proliferation and survival pathways (AKT-mediated) through OSMR and LIFR. In addition, a dramatic JAK1/STAT3 pathway activation was predominant in OSMR amplified cells and was associated with EMT features. Co-culture experiments suggested a preferential paracrine activation of the OSM-STAT3 pathway, underscoring the importance of the microenvironment. Interestingly, OSM stimulation protected cells from drug-induced apoptosis in a STAT3-dependent manner. In the BATTLE-2 translational analysis, we also found that OSMR upregulation was significantly associated to STAT3 upregulation and EMT-gene expression signatures. Conclusions: Our data suggest that the OSM-OSMR/LIFR-STAT3 pathway causes EMT and contributes to molecular targeted therapy resistance in oncogene-addicted NSCLC cells, suggesting that this pathway could be a therapeutic target in NSCLC. Ongoing experiments are assessing therapeutic vulnerabilities and refining the signaling functionally involved. Supported by NIH-NCI CA155196 & 2P50CA070907-16A1 Citation Format: Kazuhiko Shien, Vassiliki A. Papadimitrakopoulou, Dennis Ruder, Nana E. Hanson, Neda Kalhor, J. Jack Lee, Waun Ki Hong, Ximing Tang, Roy S. Herbst, Luc Girard, John D. Minna, Jonathan M. Kurie, Ignacio I. Wistuba, Julie G. Izzo. Oncostatin M receptor activation leads to molecular targeted therapy resistance in non-small cell lung cancer. [abstract] . In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 745. doi:10.1158/1538-7445.AM2015-745
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-745
    RVK:
    XA 36000
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    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    Abstract 374: VEGFR2/KDR polymorphisms and gene copy gain with outcome in non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 374-374
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 374-374
    Abstract: Background. The VEGF receptor 2 (VEGFR2) is the predominant mediator of VEGF-stimulated endothelial cell function. Recently, VEGFR2/KDR copy number gain and mutation, and VEGF copy number gain, have been described in lung adenocarcinoma tumor specimens. To better characterize the molecular changes of these two genes in non-small cell lung carcinoma (NSCLC), we investigated their abnormalities in NSCLC tumor tissue specimens and correlated with patients clinico-pathological characteristics. Methods. We extracted DNA from microdissected tissue obtained from 200 surgically resected NSCLCs. KDR single nucleotide polymorphism (SNP) 889G/A (rs2305948), SNP 1416A/T (rs1870377) and SNP −37A/G (rs2219471) were genotyped by PCR-based sequencing. KDR and VEGF copy number were examined by quantitative (q)-PCR. Protein expressions of VEGF and VEGFR2, and CD34 for microvascular density (MVD) analysis were studied by immunohistochemistry. SNP genotypes, genes copy number and protein expression were correlated with NSCLC clinico-pathological features, including overall survival (OS) and recurrence-free survival (RFS). Results. KDR 1416 AT/TT genotypes had significantly improved OS (HR = 0.56, 95% CI 0.33 to 0.96, P = 0.035) compared with KDR 1416 AA in all NSCLC patients in the multivariate analysis with adjustment of histology and tumor stage. In lung adenocarcinomas, KDR 1416 AT/TT genotypes and KDR −37AG/GG were associated with a favorable OS (HR = 0.43, 95% CI 0.20 to 0.92, P = 0.029; HR = 0.47, 95% CI 0.23 to 0.96, P = 0.039, respectively). Strikingly, KDR −37 AG/GG genotypes predicted a superior OS compared with KDR −37 AA genotype in the NSCLC patients treated with adjuvant therapy (HR = 2.45, 95% CI 1.06 to 5.66, P = 0.036). No genotype in KDR SNPs was associated with RFS in NSCLC patients. Gene copy gain of KDR and VEGF were detected respectively in 34/91 (37.4%) and 2/91 (2.2%) NSCLC tumors. Gene copy gain of KDR was associated with a poor overall survival in NSCLC patients (HR= 2.96, 95% CI 1.41 to 6.24, P = 0.004). Furthermore, tumors with gene copy gain of KDR showed significantly higher cytoplasmic (P = 0.013) and membrane (P = 0.009) VEGFR2 protein expression, lower cytoplasmic VEGF expression (P = 0.044), and higher MVD (P = 0.018) and larger vessel areas (P = 0.033) compared with tumors lacking KDR gene copy gain. Conclusion. Our findings suggest an association between KDR SNP genotypes and survival in NSCLC patients receiving adjuvant therapy. KDR copy number gain was frequently identified in NSCLC and was associated with worse survival in NSCLC patients. (Supported by grant US DoD W81XWH-07-1-0306). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 374.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-374
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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