GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-07-16)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-07-16)
    Abstract: DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-24495-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Genetic modifiers of EGFR dependence in non-small cell lung cancer
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 52 ( 2014-12-30), p. 18661-18666
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 52 ( 2014-12-30), p. 18661-18666
    Abstract: Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor ( EGFR ) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR -mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR-dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1 , FGFR2 , ITK , NTRK1 , NTRK2 , MOS , MST1R , and RAF1 . A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1412228112
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    A Functional Landscape of Resistance to ALK Inhibition in Lung Cancer
    Elsevier BV ; 2015
    In:  Cancer Cell Vol. 27, No. 3 ( 2015-03), p. 397-408
    Details
    In: Cancer Cell, Elsevier BV, Vol. 27, No. 3 ( 2015-03), p. 397-408
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccell.2015.02.005
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    High-throughput Phenotyping of Lung Cancer Somatic Mutations
    Elsevier BV ; 2017
    In:  Cancer Cell Vol. 32, No. 6 ( 2017-12), p. 884-
    Details
    In: Cancer Cell, Elsevier BV, Vol. 32, No. 6 ( 2017-12), p. 884-
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccell.2017.11.008
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Abstract 1219: Deep mutational scanning of PDE3A identifies residues required for DNMDP response
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1219-1219
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1219-1219
    Abstract: PDE3A-SLFN12 complex formation is induced by a class of compounds, now called “velcrins”, exemplified by the small molecule, DNMDP. Cancer cells that express elevated levels of PDE3A and SLFN12 are sensitive to a velcrin-mediated cytotoxic response, which is independent of PDE3A inhibition. However, the details of complex formation have not yet been revealed. We solved the crystal structure of PDE3A with a series of ligands bound to the active site and found that PDE3A exists as a dimer, and velcrin binding does not cause any obvious structural changes in the PDE3A protein structure. Hydrogen-deuterium exchange (HDX-MS) experiments with velcrin-bound PDE3A in the absence and presence of SLFN12 identified three regions of PDE3A that are shielded from solvent as a result of velcrin-induced SLFN12 binding. Two of these regions are near the velcrin binding site, and the third region lies at the PDE3A homodimerization interface. In order to further investigate the structural relationship between PDE3A, DNMDP, and SLFN12, we took a deep-mutation scanning (DMS) approach to identify residues of PDE3A that impact DNMDP sensitivity. A library of PDE3A alleles was developed in which the sequence encoding amino acids 668-1141, including the PDE3A catalytic domain, was substituted with a codon for every other possible amino acid or a stop codon in the context of the full-length cDNA. The library was transduced into PDE3A-knockout GB1 glioblastoma cells and assessed for survival in the presence of DMSO or DNMDP. Corroborating the HDX-MS data, we identified three regions of PDE3A in which missense mutations abrogated DNMDP response: the active site, the homodimerization surface, and an alpha helix containing amino acid F914. We confirmed that mutations of F914 and the homodimer interface retain the ability to bind resin-conjugated compound but fail to complex with SLFN12. Taken together, the HDX and DMS results suggest that PDE3A dimerization is required to stabilize velcrin-induced SLFN12 binding and implicate the alpha helix containing F914 as the SLFN12 binding interface of PDE3A. Citation Format: Xiaoyun Wu, Malvina Papanastasiou, Gavin Schnitzler, Colin Garvie, Stephanie Hoyt, Terry Zhang, James Mullahoo, Andrew Baker, Joseph McGaunn, Bethany Kaplan, Sooncheol Lee, Martin Lange, Steven Carr, Xiaoping Yang, Federica Piccioni, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. Deep mutational scanning of PDE3A identifies residues required for DNMDP response [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 1219.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1219
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Abstract PR04: High-throughput gene expression profiling as a generalizable assay for determination of mutation impact on gene function
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 22_Supplement_2 ( 2015-11-15), p. PR04-PR04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22_Supplement_2 ( 2015-11-15), p. PR04-PR04
    Abstract: Recently, the decline in the cost of genome sequencing has led to the rapid identification of thousands of cancer-associated somatic mutations. However, progress in characterization of these genetic events has lagged significantly behind. Understanding mutation function is critical not only for research purposes but also for determining targeted treatment strategies based on individual tumor genetic profiles, yet determination of mutation impact remains a significant bottleneck. Here we describe a high-throughput approach to classify somatic mutations that is robust, scalable, and requires no prior information of gene function. We generated a lentiviral cDNA expression library of ~550 mutated and wild-type alleles of genes mutated in lung adenocarcinoma and introduced these alleles into four human lung cell lines. 96 hours post-infection, gene expression profiles were generated using Luminex-based L1000 profiling. In total, more than 2000 gene expression signatures were generated. We discovered that gain-of-function mutants induce expression signatures with a greater signal strength or different identity than the corresponding wild-type gene signature. In contrast, loss-of-function mutants could be identified by their incapability to induce strong signatures. Based on these features of signature strength and signature identity, we developed a decision-tree approach to classify mutations as either dominant, loss-of-function, or likely inert. An orthogonal functional approach, an EGFR inhibitor resistance screen, was used as validation. The gene expression approach correctly classified known gain-of-function mutations in KRAS (13/13), EGFR (6/7), and ARAF (2/2) and identified dozens of never-characterized gain-of-function and loss-of-function missense mutations. In addition to rare, dominant mutations in clinically-actionable oncogenes such as PIK3CA and AKT1, we identified unexpected dominant mutations in the transcription factor MAX and the phosphatase subunit PPP2R1A, among others. We also observed a substantial enrichment of loss-of-function mutations in tumor suppressor genes such as STK11, KEAP1, FBXW7, and CASP8 as well as in genes not previously connected to lung adenocarcinoma, including GPR137B and MAPK7. Most genes assayed also harbored variants that are likely inert, further underscoring the importance of characterizing individual variant alleles. The method developed here can, in principle, characterize any genetic variant, independent of prior knowledge of gene function, and should significantly advance the pace of functional characterization of mutations identified from genome sequencing. Citation Format: Alice Berger, Angela Brooks, Xiaoyun Wu, Larson Hogstrom, Itay Tirosh, Federica Piccioni, Mukta Bagul, Cong Zhu, Yashaswi Shretha, David Root, Pablo Tamayo, Ryo Sakai, Bang Wong, Aravind Subramanian, Todd Golub, Matthew Meyerson, Jesse Boehm. High-throughput gene expression profiling as a generalizable assay for determination of mutation impact on gene function. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.COMPSYSBIO-PR04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Abstract 4368: High-throughput phenotyping of lung cancer somatic mutations
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4368-4368
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4368-4368
    Abstract: Recent cancer genome sequencing and analysis has identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood, limiting the use of this genetic knowledge for clinical decision-making. Here we describe a new high-throughput approach, expression-based variant impact phenotyping (eVIP), which uses gene expression changes to infer somatic mutation impact. We generated a lentiviral expression library representing 53 genes and 194 somatic mutations identified in primary lung adenocarcinomas. Next, we introduced this library into A549 lung adenocarcinoma cells and 96 hours later performed gene expression profiling using Luminex-based L1000 profiling. We built a computational pipeline, eVIP, to compare mutant and wild-type expression signatures to infer whether variants were gain-of-function, change-of-function, loss-of-function, or neutral. Overall, eVIP identified 69% of mutations as impactful whereas 31% appeared functionally neutral. A very high rate, 92%, of missense mutations in the KEAP1 and STK11 tumor suppressor genes were found to inactivate or diminish protein function. As a complementary approach, we assessed which mutations are epistatic to EGFR or capable of initiating xenograft tumor formation in vivo. A subset of the impactful mutations identified by eVIP could induce xenograft tumor formation in mice and/or confer resistance to cellular EGFR inhibition. Among these mutations were 20 rare or non-canonical somatic variants in clinically-actionable or -relevant oncogenes including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and PIK3CA E600K. eVIP can, in principle, characterize any genetic variant, independent of prior knowledge of gene function. Further application of eVIP should significantly advance the pace of functional characterization of mutations identified from genome sequencing. Citation Format: Alice H. Berger, Angela N. Brooks, Xiaoyun Wu, Yashaswi Shrestha, Candace Chouinard, Federica Piccioni, Mukta Bagul, Atanas Kamburov, Marcin Imielinski, Larson Hogstrom, Cong Zhu, Xiaoping Yang, Sasha Pantel, Ryo Sakai, Nathan Kaplan, David Root, Rajiv Narayan, Ted Natoli, David Lahr, Itay Tirosh, Pablo Tamayo, Gad Getz, Bang Wong, John Doench, Aravind Subramanian, Todd R. Golub, Matthew Meyerson, Jesse S. Boehm. High-throughput phenotyping of lung cancer somatic mutations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4368.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-4368
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Research Vol. 17, No. 11 ( 2019-11-01), p. 2281-2293
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 11 ( 2019-11-01), p. 2281-2293
    Abstract: High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including BCL2L1 (BCL-XL) and BCL2L2 (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of BCL2L1 decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. Implications: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-18-1243
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2097884-4
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Abstract AP14: POOLED GENOMIC SCREENS IDENTIFY ANTI-APOPTOTIC GENES AS MEDIATORS OF CHEMOTHERAPY RESISTANCE IN OVARIAN CANCER
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 22_Supplement ( 2019-11-15), p. AP14-AP14
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 22_Supplement ( 2019-11-15), p. AP14-AP14
    Abstract: *Co-senior authors Primary high-grade serous ovarian cancer (HGSOC) is often sensitive to platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. Although alterations in DNA repair function, gene expression, apoptosis, and other pathways have been described that can mediate chemotherapy resistance in HGSOC, the full landscape of HGSOC drug resistance mechanisms and the optimal strategies to eliminate resistant disease have not been fully elucidated. We performed systematic, unbiased near-genome-scale pooled overexpression and CRISPR/Cas9 knockout screens in two BRCA2-mutant HGSOC cell lines to identify genes promoting survival following cisplatin, paclitaxel, or cisplatin/paclitaxel treatment. Anti-apoptotic genes including BCL2L1 (BCL-XL), and BCL2L2 (BCL-W) were among the top hits mediating chemotherapy resistance in the overexpression screen. In the CRISPR/Cas9 screen, loss of pro-apoptotic genes (caspases, APAF1) conferred resistance, and knockout of BCL2L1 sensitized to platinum. A secondary overexpression screen of ~400 genes confirmed anti-apoptotic proteins BCL-XL, BCL-W and BCL-2 as top resistance genes, and validated numerous other candidates. Of note, anti-apoptotic genes BCL2L1 and MCL1 are focally amplified and overexpressed in patients with primary HGSOC. In HGSOC cell lines, overexpression of BCL-XL or BCL-W, and to a lesser extent BCL-2 or MCL1, conferred platinum and taxane resistance and decreased chemotherapy-induced apoptosis in HGSOC cell lines. We systematically tested small molecule inhibitors of BCL-2, BCL-XL, MCL1, or BCL2/BCL-XL as single agents or combined with chemotherapy in HGSOC cell lines. Inhibiting BCL-XL, MCL1, or BCL2/BCL-XL, but not BCL-2, significantly increased cell death when combined with cisplatin or paclitaxel. BCL-XL, MCL1, or BCL2/BCL-XL inhibitors also synergized with olaparib, a poly- ADP-ribose inhibitor. Concomitant overexpression of BCL-XL, BCL-W, or MCL1 abrogated the sensitizing effect of the anti-apoptotic protein inhibitors, depending upon the specific inhibitor. Taken together, unbiased near-genome-scale overexpression screens and patient genomic data highlight the role of the intrinsic pathway of apoptosis in HGSOC chemotherapy resistance. Our studies validate that anti-apoptotic proteins mediate resistance to several clinically relevant drugs in HGSOC, and support that BCL-XL and MCL1 may be therapeutic targets in HGSOC, particularly in combination with DNA-damaging agents. Citation Format: Elizabeth H. Stover, Maria B. Baco, Ofir Cohen, Yvonne Li, Elizabeth Christie, Mukta Bagul, Amy Goodale, Yenarae Lee, Sasha Pantel, Matthew Rees, Guo Wei, Adam Presser, Ioannis Zervantonakis, Patrick Bhola, Jeremy Ryan, Jennifer Guerriero, Felice Liang, Andrew Cherniack, Federica Piccioni, Ursula A. Matulonis, David D. L. Bowtell, Anthony Letai, Kris Sarosiek, Levi Garraway, Cory M. Johannessen, Matthew Meyerson. POOLED GENOMIC SCREENS IDENTIFY ANTI-APOPTOTIC GENES AS MEDIATORS OF CHEMOTHERAPY RESISTANCE IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP14.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.OVCASYMP18-AP14
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    RAS–MAPK Reactivation Facilitates Acquired Resistance in FGFR1 -Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR–MEK Blockade
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Therapeutics Vol. 17, No. 7 ( 2018-07-01), p. 1526-1539
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 17, No. 7 ( 2018-07-01), p. 1526-1539
    Abstract: The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a FGFR1-dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS–MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. Mol Cancer Ther; 17(7); 1526–39. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-17-0464
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...