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  • 1
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    GCNA Preserves Genome Integrity and Fertility Across Species
    Elsevier BV ; 2020
    In:  Developmental Cell Vol. 52, No. 1 ( 2020-01), p. 38-52.e10
    Details
    In: Developmental Cell, Elsevier BV, Vol. 52, No. 1 ( 2020-01), p. 38-52.e10
    Type of Medium: Online Resource
    ISSN: 1534-5807
    URL: Article
    DOI: 10.1016/j.devcel.2019.11.007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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    SSG: 12
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  • 2
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    Elucidating Mechanisms of Acquired Resistance to IDH Inhibition By Saturation Variant Screening of Base-Edited Leukemia Cells
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 3-3
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 3-3
    Abstract: Somatic mutations in catalytic arginine residues of isocitrate dehydrogenases IDH1 and IDH2 occur frequently in myeloid malignancies. Heterozygous mutation of cytosolic IDH1 or mitochondrial IDH2 contributes to leukemia development by accumulating the oncometabolite (R)-2-hydroxyglutarate (R-2-HG), causing alterations of histone and DNA methylation through impaired α-ketoglutarate-dependent dioxygenases. Small molecule inhibitors ivosidenib and enasidenib, which specifically target mutant IDH1 and IDH2 respectively, are now approved for the treatment of newly diagnosed and/or relapsed/refractory acute myeloid leukemia (AML) patients with IDH1/2 mutations. However, multiple cases of therapeutic resistance to IDH inhibitors were reported. Distinct mechanisms were described for clinical resistance of IDH inhibition, such as the acquisition of secondary mutations in cis or trans on the allosteric binding site of IDH inhibitors or isoform switching. Although a few amino acid substitutions including IDH1-S280F, IDH2-Q316E and IDH2-I319M were identified to be associated with acquired resistance, the extent to which the mutational repertoire at IDH1/2 proteins and the associated mechanisms contribute to acquired resistance to IDH inhibition remains unknown. In this study, we systematically examined all potential amino acid substitution mutations on IDH1 and IDH2 by multiple orthogonal saturating mutagenesis screens in base-edited myeloid leukemia cells. We first engineered independent myeloid leukemia cell lines containing endogenous patient-derived IDH1/2 mutations by CRISPR/Cas9-mediated base-editing. We created clonal leukemia cell lines containing heterozygous IDH1-R132H (IDH1R132H/WT) or IDH2-R140Q (IDH2R140Q/WT) mutations, which are the most frequent IDH1/2 mutations in AML. The base-edited IDH1 or IDH2-mutant leukemia cells were characterized by the accumulation of the oncometabolite R-2-HG, alterations of histone and DNA methylation, and aberrant cytokine-independent cell growth. To identify all possible amino acid substitution mutations with resistance to IDH inhibition, we performed MITE-seq-based saturation variant screens, in which each amino acid was systematically substituted by all other possible amino acids, in base-edited leukemia cells. We not only validated known mutations such as IDH1-S280F, IDH2-Q316E and IDH2-I319M, but also identified a list of de novo amino acid substitutions associated with acquired resistance to IDH inhibition. Furthermore, the base-edited leukemia cells were treated continuously with ivosidenib and enasidenib up to 16 weeks to identify acquired resistance-associated IDH1/2 mutations by next-generation sequencing. Finally, we performed ultra-deep targeted sequencing of IDH1/2 genes in 11 paired diagnosis and relapsed AML samples in patients treated with ivosidenib or enasidenib as monotherapy, and identified significantly enriched IDH1/2 secondary mutations in the relapsed samples as compared to AML samples at diagnosis. Integrative analyses of multiple orthogonal mutagenesis screens uncovered a compendium of high-confidence and clinically relevant IDH1/2 mutations with resistance to IDH inhibition. Structural modelling of IDH1/2 mutation-associated protein domains provided new insights into the mechanisms for acquired resistance due to dysregulated protein 3D structure, co-factor binding, and/or steric hindrance with the binding of small molecular inhibitors. Follow-up functional studies established new IDH mutations as candidate drivers of acquired resistance to IDH inhibition through distinct mechanisms in AML. Taken together, we generated isogenic, base-edited IDH1/2 mutant myeloid leukemia cells and identified candidate amino acid substitutions conferring resistance to IDH inhibition through orthogonal saturating variant screens. We integrated the results with targeted sequencing of IDH1/2 mutations in AML patients, structural modeling, and functional studies. Our findings not only uncover de novo pathogenic mutations associated with resistance to IDH inhibition, but also provide new insights into the molecular mechanisms for acquired resistance to a targeted therapy in AML. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-141433
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 3
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    Abstract PD7-04: Fibroblast growth factor receptor 1 associates with promoters genome-wide and regulates gene transcription in ER+/FGFR1-amplified breast cancer: Implications for endocrine resistance
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. PD7-04-PD7-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. PD7-04-PD7-04
    Abstract: Background: FGFR1 amplification occurs in about 15% of estrogen receptor-positive (ER+) breast cancers and is associated with resistance to endocrine therapy. In these tumors, nuclear FGFR1 has been shown to interact with ERα and alter gene expression through binding to chromatin. However, the mechanisms underpinning nuclear FGFR1-mediated gene transcription remain unclear. Thus, we sought to elucidate mechanisms to explain the genomic role of FGFR1 in ER+/FGFR1-amplified breast cancer.Results: FGFR1 ChIP-Seq detected 4408 DNA binding sites in CAMA1 ER+/FGFR1-amplified breast cancer cells cultured in estrogen-free conditions; 67% of these sites were enriched at promoter regions, suggesting a role of FGFR1 in gene transcription regulation. ChIP-qPCR assay confirmed FGFR1 binding to promoter regions of genes such as CCND1, MYC, VEGFA, JUNB and SMAD5 in both CAMA1 and MDA-MB-134 ER+/FGFR1-amplified cells and also in an ER+/FGFR1-amplified patient derived xenograft (HCI-011). RNA-Seq of CAMA1 cells revealed that expression of FGFR1-bound genes was substantially higher than non FGFR1-bound genes (p & lt;0.0001), suggesting FGFR1 binds to genes that are actively transcribed. Consistent with these results, precipitation with a FGFR1 antibody followed by immunoblot analysis showed association of FGFR1 with RNA Polymerase II (Pol II) in CAMA1, MDA-MB-134 and HCI-011 cell extracts. FGFR1 mainly bound with Pol II phosphorylated in Ser5 (Pol II S5P), a post-translational modification required for transcriptional activity. ChIP-Seq in CAMA1 cells with a Pol II S5P antibody revealed that 2867 of 4408 (65%) FGFR1 binding sites overlapped with Pol II S5P peaks, with a distribution centered on a similar location near the transcription start site. This interaction was validated by ChIP-reChIP assay, via sequential immunoprecipitation of FGFR1 and Pol II. Analysis of the METABRIC cohort showed that 1096/4408 (25%) FGFR1 DNA binding sites overlapped with genes differentially expressed in FGFR1-amplified vs FGFR1 non-amplified ER+ breast cancers. From this 1096-overexpressed gene list and using Gene Set Variation Analysis (GSVA), we developed a signature score for the top 102 genes (LogFC & gt;0.25), representing those whose expression is likely regulated by FGFR1. This high signature score was associated with worse disease free survival (DFS; 263.7 months vs not reached; HR=1.72, CI 1.39-2.12; p & lt;0.0001) and overall survival (OS; 145.1 vs 174.1 months; HR=1.24, CI 1.07-1.43; p=0.0003) in the ER+/HER2− cohort in METABRIC. This high signature score also correlated with high tumor grade (p & lt;0.0001) and a worse Nottingham prognostic index (p & lt;0.0001). Finally, we investigated cofactors influencing FGFR1 genomic function. Since nuclear FGFR1 has been shown to interact with ERα, we examined those cofactors involved in ER transcription. We initially focused on the FOXA1 pioneer factor, which mediates transcription factor binding to chromatin in ER+ breast cancer cells. Precipitation with a FGFR1 antibody followed by FOXA1 immunoblot analysis demonstrated an association of FGFR1 with FOXA1 in CAMA1 and MDA-MB-134 cells. ChIP in CAMA1 cells revealed FOXA1 enrichment at promoter regions bound by FGFR1. Further, siRNA-mediated FOXA1 knockdown in CAMA1 cells markedly reduced FGFR1 binding to several promoter regions, preliminarily including CCND1, JUNB, SMAD5, MYC and TOB1, as measured by ChIP-qPCR. Conclusions: These findings suggest a prominent role of FGFR1 in gene transcription regulation in breast cancer. Whether this transcriptional action is causal to antiestrogen resistance in ER+/FGFR1-amplified breast cancer is under active investigation and will be reported at the Symposium. Citation Format: Alberto Servetto, Rahul Kollipara, Luigi Formisano, Kyung-min Lee, Dhivya R Sudhan, Ariella B Hanker, Sumanta Chatterjee, Albert Lin, Saurabh Mendiratta, Nicholas James, Ralf Kittler, Carlos L Arteaga. Fibroblast growth factor receptor 1 associates with promoters genome-wide and regulates gene transcription in ER+/FGFR1-amplified breast cancer: Implications for endocrine resistance [abstract] . In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-PD7-04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Abstract 1304: FGFR1 associates with gene promoters and regulates transcription in ER+/FGFR1-amplified breast cancer: Implications for endocrine resistance
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1304-1304
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1304-1304
    Abstract: Background: FGFR1 amplification occurs in ~ 15% of estrogen receptor-positive (ER+) breast cancers. In these tumors, nuclear FGFR1 has been shown to interact with DNA, but its engagement in transcription regulation remains unclear. Thus, we investigated the mechanisms underpinning the genomic role of FGFR1 in ER+/FGFR1-amplified breast cancer. Methods: FGFR1-ChIP-Seq was performed in CAMA1 ER+/FGFR1-amplified human breast cancer cells to identify genomic distribution of FGFR1. IP with FLAG antibody followed by Mass Spectrometry (MS) was carried out on nuclear plus chromatin fractions of CAMA1 cells overexpressing 3XFLAG-FGFR1 to uncover the nuclear FGFR1 interactome. Results: FGFR1-ChIP-Seq detected 4408 peaks in CAMA1 cells cultured in estrogen-free conditions, with marked enrichment of GC-rich consensus motifs. 67% of peaks were enriched at promoter regions. ChIP-PCR confirmed FGFR1 binding to several genomic loci in ER+/FGFR1-amplified cell lines (CAMA1 and MDA-MB-134) and PDX (HCI-011). Further, MS uncovered RNA Polymerase II subunits among the top nuclear FGFR1 interacting proteins. FGFR1 mainly bound Pol II phosphorylated on Ser5 (Pol II S5P), a marker of transcription initiation, in CAMA1, MDA-MB-134 and HCI-011 cell extracts. Pol II S5P-ChIP-Seq revealed that 65% (2867/4408) of FGFR1 peaks were shared with Pol II S5P in CAMA1 cells. Also, ChIP-Seq revealed that 95% of FGFR1 peaks overlapped with both H3K4me3 and H3K27ac, markers of active transcription. Consistent with these results, RNA-Seq of CAMA1 cells showed that expression of FGFR1-bound genes was markedly higher than non FGFR1-bound genes (p & lt;0.0001), suggesting that FGFR1 binds to actively transcribed genes. The pioneer factor FOXA1 was detected by MS among FGFR1 interacting proteins and ChIP-Seq showed its enrichment at FGFR1-bound promoters. Notably, siRNA-mediated FOXA1 knockdown reduced FGFR1 distribution to several genomic loci in CAMA1 cells, as measured by FGFR1-ChIP-Seq. Finally, we found that 10% (360/3558) of FGFR1 peaks overlapped with genes that were differentially expressed in FGFR1-amplified (n=7) vs FGFR1 non-amplified (n=30) ER+ breast tumors treated with neoadjuvant letrozole. Using Gene Set Variation Analysis, we developed a signature score for the top 32/360 genes (LogFC & gt;1), whose expression is likely regulated by nuclear FGFR1. A high signature score correlated with resistance to letrozole (p & lt;0.0001) and high post-treatment Ki67 index (p=0.0004) in our cohort, and with worse disease-free and overall survival in the METABRIC cohort of ER+/HER2− patients treated with endocrine therapy. Conclusions: These findings support a prominent role for FGFR1 in the transcriptional machinery of breast cancer cells. Whether this transcriptional action is causal to antiestrogen resistance in ER+/FGFR1-amplified breast cancer is currently under investigation. Citation Format: Alberto Servetto, Rahul Kollipara, Luigi Formisano, Kyung-min Lee, Albert Lin, Dhivya R. Sudhan, Ariella B. Hanker, Sumanta Chatterjee, Hiroaki Akamatsu, Arnaldo Marin, Saurabh Mendiratta, Ralf Kittler, Carlos L. Arteaga. FGFR1 associates with gene promoters and regulates transcription in ER+/FGFR1-amplified breast cancer: Implications for endocrine resistance [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 1304.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-1304
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    Abstract GS1-06: FGFR1 associates with gene promoters and regulates gene transcription: Implications for endocrine resistance in ER+/FGFR1-amplified breast cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 4_Supplement ( 2021-02-15), p. GS1-06-GS1-06
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. GS1-06-GS1-06
    Abstract: Background: FGFR1 amplification occurs in ~ 15% of ER+ breast cancers. In these tumors, nuclear FGFR1 has been shown to interact with DNA, but its role in transcriptional regulation is unclear. Thus, we investigated the genomic role of FGFR1 in ER+/FGFR1-amplified breast cancer. Results: FGFR1 ChIP-Seq detected 4,412 DNA binding sites in CAMA1 ER+/FGFR1-amplified breast cancer cells cultured in estrogen-free conditions. Of these binding sites, 67% were enriched at promoter regions. ChIP-qPCR confirmed FGFR1 binding to several promoter regions in a second ER+/FGFR1-amplified cell line, MDA-MB-134, and a patient derived xenograft, HCI-011. To determine the nuclear FGFR1 interactome, we performed FLAG immunoprecipitation of mixed nuclear and chromatin fractions of CAMA1 cells transduced with a 3XFLAG-FGFR1 plasmid, followed by mass spectrometry (MS) of FLAG antibody pulldowns. MS revealed RNA Polymerase II subunits among the top nuclear FGFR1 interacting proteins. FGFR1 mainly bound Pol II phosphorylated on Ser5 (Pol II S5P), a marker of transcription initiation, in CAMA1, MDA-MB-134 and HCI-011 cell extracts. Pol II S5P ChIP-Seq revealed that 2,867/4,412 (65%) FGFR1 peaks were shared with Pol II S5P. ChIP-Seq also showed that 95% of FGFR1 peaks overlapped with both H3K4me3 and H3K27ac, markers of active transcription. Consistent with these results, RNA-Seq of CAMA1 cells showed that expression of FGFR1-bound genes was markedly higher than non FGFR1-bound genes (p & lt;0.0001), suggesting that FGFR1 binds to actively transcribed genes. In addition to Pol II, MS detected FOXA1 among FGFR1 interacting proteins. ChIP-Seq analysis revealed FOXA1 enriched at FGFR1-bound loci. siRNA-mediated FOXA1 knockdown reduced FGFR1 distribution to several genomic loci in CAMA1 cells, as measured by FGFR1 ChIP-Seq, suggesting that FOXA1 mediates FGFR1 recruitment to chromatin. We next transduced MCF-7 cells with an FGFR1(SP-)(NLS) plasmid, where the NLS sequence forces nuclear import of the resulting protein. To determine the role of FGFR1 on transcriptional regulation, we used Binding and Expression Target Analysis (BETA), integrating FGFR1 ChIP-Seq and RNA-Seq results from MCF7FGFR1(SP-)(NLS) vs MCF7EV cells. This analysis predicted a direct role for genomic-bound FGFR1 in activating gene expression (p=8.01e-6). MCF7FGFR1(SP-)(NLS) cells were markedly less sensitive to fulvestrant compared to control cells. Gene Set Enrichment Analysis (GSEA) of the 1,009 genes upregulated in MCF7FGFR1(SP-)(NLS) cells and bound by FGFR1 at a genomic level revealed a strong enrichment of estrogen response early (q=2.2e-44) and late (q=6.4e-33) genes, suggesting that nuclear FGFR1 induces an ERα-associated transcriptional profile that may contribute to endocrine resistance. Finally, an expression signature associated with nuclear FGFR1 correlated with endocrine resistance in three cohorts of patients with ER+ breast cancer treated with aromatase inhibitors. We next studied the effect of growth factor stimulation on FGFR1 transcriptional function. Stimulation with FGF2 enhanced nuclear FGFR1 import in CAMA1 cells, as well as FGFR1-Pol II S5P association. Notably, these effects were not abrogated by treatment with the FGFR1 inhibitor erdafitinib. ChIP-Seq revealed that erdafitinib did not impair the FGFR1 genomic distribution. These results do not support a causal link between the FGFR1 activated TK and the receptor’s activity in the nucleus. Conclusions: We have demonstrated a role for nuclear FGFR1 in transcriptional regulation in breast cancer. FGFR1-induced gene expression contributes to endocrine resistance and is not affected by FGFR TKIs. These findings provide a rationale for developing treatment strategies to inhibit nuclear FGFR1 in ER+/FGFR1-amplified breast cancer. Citation Format: Alberto Servetto, Rahul Kollipara, Luigi Formisano, Chang-Ching Lin, Kyung-min Lee, Dhivya R Sudhan, Ariella B Hanker, Sumanta Chatterjee, Angel Guerrero-Zotano, Paula Gonzalez-Ericsson, Saurabh Mendiratta, Hiroaki Akamatsu, Nicholas James, Ralf Kittler, Carlos L Arteaga. FGFR1 associates with gene promoters and regulates gene transcription: Implications for endocrine resistance in ER+/FGFR1-amplified breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-06.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS20-GS1-06
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 23 ( 2021-12-01), p. 5935-5947
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 23 ( 2021-12-01), p. 5935-5947
    Abstract: Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21−/− mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. Significance: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-0752
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    Inhibition of Karyopherin β1-Mediated Nuclear Import Disrupts Oncogenic Lineage-Defining Transcription Factor Activity in Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 17 ( 2022-09-02), p. 3058-3073
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 17 ( 2022-09-02), p. 3058-3073
    Abstract: Genomic studies support the classification of small cell lung cancer (SCLC) into subtypes based on the expression of lineage-defining transcription factors ASCL1 and NEUROD1, which together are expressed in ∼86% of SCLC. ASCL1 and NEUROD1 activate SCLC oncogene expression, drive distinct transcriptional programs, and maintain the in vitro growth and oncogenic properties of ASCL1 or NEUROD1-expressing SCLC. ASCL1 is also required for tumor formation in SCLC mouse models. A strategy to inhibit the activity of these oncogenic drivers may therefore provide both a targeted therapy for the predominant SCLC subtypes and a tool to investigate the underlying lineage plasticity of established SCLC tumors. However, there are no known agents that inhibit ASCL1 or NEUROD1 function. In this study, we identify a novel strategy to pharmacologically target ASCL1 and NEUROD1 activity in SCLC by exploiting the nuclear localization required for the function of these transcription factors. Karyopherin β1 (KPNB1) was identified as a nuclear import receptor for both ASCL1 and NEUROD1 in SCLC, and inhibition of KPNB1 led to impaired ASCL1 and NEUROD1 nuclear accumulation and transcriptional activity. Pharmacologic targeting of KPNB1 preferentially disrupted the growth of ASCL1+ and NEUROD1+ SCLC cells in vitro and suppressed ASCL1+ tumor growth in vivo, an effect mediated by a combination of impaired ASCL1 downstream target expression, cell-cycle activity, and proteostasis. These findings broaden the support for targeting nuclear transport as an anticancer therapeutic strategy and have implications for targeting lineage-transcription factors in tumors beyond SCLC. Significance: The identification of KPNB1 as a nuclear import receptor for lineage-defining transcription factors in SCLC reveals a viable therapeutic strategy for cancer treatment.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-3713
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
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    Nuclear FGFR1 Regulates Gene Transcription and Promotes Antiestrogen Resistance in ER+ Breast Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 15 ( 2021-08-01), p. 4379-4396
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 15 ( 2021-08-01), p. 4379-4396
    Abstract: FGFR1 overexpression has been associated with endocrine resistance in ER+ breast cancer. We found FGFR1 localized in the nucleus of breast cancer cells in primary tumors resistant to estrogen suppression. We investigated a role of nuclear FGFR1 on gene transcription and antiestrogen resistance. Experimental Design: Tumors from patients treated with letrozole were subjected to Ki67 and FGFR1 IHC. MCF7 cells were transduced with FGFR1(SP-)(NLS) to promote nuclear FGFR1 overexpression. FGFR1 genomic activity in ER+/FGFR1-amplified breast cancer cells ± FOXA1 siRNA or ± the FGFR tyrosine kinase inhibitor (TKI) erdafitinib was examined by chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq). The nuclear and chromatin-bound FGFR1 interactome was investigated by mass spectrometry (MS). Results: High nuclear FGFR1 expression in ER+ primary tumors positively correlated with post-letrozole Ki67 values. Nuclear FGFR1 overexpression influenced gene transcription and promoted resistance to estrogen suppression and to fulvestrant in vivo. A gene expression signature induced by nuclear FGFR1 correlated with shorter survival in the METABRIC cohort of patients treated with antiestrogens. ChIP-Seq revealed FGFR1 occupancy at transcription start sites, overlapping with active transcription histone marks. MS analysis of the nuclear FGFR1 interactome identified phosphorylated RNA-Polymerase II and FOXA1, with FOXA1 RNAi impairing FGFR1 recruitment to chromatin. Treatment with erdafitinib did not impair nuclear FGFR1 translocation and genomic activity. Conclusions: These data suggest nuclear FGFR1 contributes to endocrine resistance by modulating gene transcription in ER+ breast cancer. Nuclear FGFR1 activity was unaffected by FGFR TKIs, thus supporting the development of treatment strategies to inhibit nuclear FGFR1 in ER+/FGFR1 overexpressing breast cancer.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-3905
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 9
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    Table_2.xlsx
    Frontiers Media SA ; 2023
    In:  Frontiers in Oncology Vol. 13 ( 2023-3-23)
    Details
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 13 ( 2023-3-23)
    Abstract: The glucocorticoid receptor (GR) is an important anti-cancer target in lymphoid cancers but has been understudied in solid tumors like lung cancer, although glucocorticoids are often given with chemotherapy regimens to mitigate side effects. Here, we identify a dexamethasone-GR mediated anti-cancer response in a subset of aggressive non-small cell lung cancers (NSCLCs) that harbor Serine/Threonine Kinase 11 (STK11/LKB1) mutations. High tumor expression of carbamoyl phosphate synthase 1 (CPS1) was strongly linked to the presence of LKB1 mutations, was the best predictor of NSCLC dexamethasone (DEX) sensitivity ( p & lt; 10 -16 ) but was not mechanistically involved in DEX sensitivity. Subcutaneous, orthotopic and metastatic NSCLC xenografts, biomarker-selected, STK11/LKB1 mutant patient derived xenografts, and genetically engineered mouse models with KRAS/LKB1 mutant lung adenocarcinomas all showed marked in vivo anti-tumor responses with the glucocorticoid dexamethasone as a single agent or in combination with cisplatin. Mechanistically, GR activation triggers G1/S cell cycle arrest in LKB1 mutant NSCLCs by inducing the expression of the cyclin-dependent kinase inhibitor, CDKN1C /p57(Kip2). All findings were confirmed with functional genomic experiments including CRISPR knockouts and exogenous expression. Importantly, DEX-GR mediated cell cycle arrest did not interfere with NSCLC radiotherapy, or platinum response in vitro or with platinum response in vivo . While DEX induced LKB1 mutant NSCLCs in vitro exhibit markers of cellular senescence and demonstrate impaired migration, in vivo DEX treatment of a patient derived xenograft (PDX) STK11/LKB1 mutant model resulted in expression of apoptosis markers. These findings identify a previously unknown GR mediated therapeutic vulnerability in STK11/LKB1 mutant NSCLCs caused by induction of p57(Kip2) expression with both STK11 mutation and high expression of CPS1 as precision medicine biomarkers of this vulnerability.
    Type of Medium: Online Resource
    ISSN: 2234-943X
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    URL: Article
    URL: Article
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    DOI: 10.3389/fonc.2023.1025443
    DOI: 10.3389/fonc.2023.1025443.s001
    DOI: 10.3389/fonc.2023.1025443.s002
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    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
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    In: Cancer Letters, Elsevier BV, Vol. 552 ( 2023-01), p. 215984-
    Type of Medium: Online Resource
    ISSN: 0304-3835
    URL: Article
    DOI: 10.1016/j.canlet.2022.215984
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