RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade

Bruno Bockorny; Maria Rusan; Wankun Chen; Rachel G Liao; Yvonne Li; Federica Piccioni; Jun Wang; Li Tan; Aaron R Thorner; Tianxia Li; Yanxi Zhang; Changhong Miao; Therese Ovesen; Geoffrey I Shapiro; David J Kwiatkowski; Nathanael S Gray; Matthew Meyerson; Peter S Hammerman; Adam J Bass

doi:10.1158/1535-7163.MCT-17-0464

RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade

Bruno Bockorny, Maria Rusan, Wankun Chen, Rachel G Liao, Yvonne Li, Federica Piccioni, Jun Wang, Li Tan, Aaron R Thorner, Tianxia Li, Yanxi Zhang, Changhong Miao, Therese Ovesen, Geoffrey I Shapiro, David J Kwiatkowski, Nathanael S Gray, Matthew Meyerson, Peter S Hammerman, Adam J Bass

Department of Clinical Medicine

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

47 Citations (Scopus)

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.

Original language	English
Journal	Molecular Cancer Therapeutics
Volume	17
Issue	7
Pages (from-to)	1526-1539
Number of pages	14
ISSN	1535-7163
DOIs	https://doi.org/10.1158/1535-7163.MCT-17-0464
Publication status	Published - Jul 2018

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10.1158/1535-7163.MCT-17-0464

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030474/pdf/nihms959877.pdf

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Bockorny, B., Rusan, M., Chen, W., Liao, R. G., Li, Y., Piccioni, F., Wang, J., Tan, L., Thorner, A. R., Li, T., Zhang, Y., Miao, C., Ovesen, T., Shapiro, G. I., Kwiatkowski, D. J., Gray, N. S., Meyerson, M., Hammerman, P. S., & Bass, A. J. (2018). RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade. Molecular Cancer Therapeutics, 17(7), 1526-1539. https://doi.org/10.1158/1535-7163.MCT-17-0464

@article{ea86fdd94fa545869e19365f1a63c644,

title = "RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade",

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.",

author = "Bruno Bockorny and Maria Rusan and Wankun Chen and Liao, {Rachel G} and Yvonne Li and Federica Piccioni and Jun Wang and Li Tan and Thorner, {Aaron R} and Tianxia Li and Yanxi Zhang and Changhong Miao and Therese Ovesen and Shapiro, {Geoffrey I} and Kwiatkowski, {David J} and Gray, {Nathanael S} and Matthew Meyerson and Hammerman, {Peter S} and Bass, {Adam J}",

note = "{\textcopyright}2018 American Association for Cancer Research.",

year = "2018",

month = jul,

doi = "10.1158/1535-7163.MCT-17-0464",

language = "English",

volume = "17",

pages = "1526--1539",

journal = "Molecular Cancer Therapeutics",

issn = "1535-7163",

publisher = "American Association for Cancer Research Inc.",

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Bockorny, B, Rusan, M, Chen, W, Liao, RG, Li, Y, Piccioni, F, Wang, J, Tan, L, Thorner, AR, Li, T, Zhang, Y, Miao, C, Ovesen, T, Shapiro, GI, Kwiatkowski, DJ, Gray, NS, Meyerson, M, Hammerman, PS & Bass, AJ 2018, 'RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade', Molecular Cancer Therapeutics, vol. 17, no. 7, pp. 1526-1539. https://doi.org/10.1158/1535-7163.MCT-17-0464

RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade. / Bockorny, Bruno; Rusan, Maria; Chen, Wankun et al.
In: Molecular Cancer Therapeutics, Vol. 17, No. 7, 07.2018, p. 1526-1539.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade

AU - Bockorny, Bruno

AU - Rusan, Maria

AU - Chen, Wankun

AU - Liao, Rachel G

AU - Li, Yvonne

AU - Piccioni, Federica

AU - Wang, Jun

AU - Tan, Li

AU - Thorner, Aaron R

AU - Li, Tianxia

AU - Zhang, Yanxi

AU - Miao, Changhong

AU - Ovesen, Therese

AU - Shapiro, Geoffrey I

AU - Kwiatkowski, David J

AU - Gray, Nathanael S

AU - Meyerson, Matthew

AU - Hammerman, Peter S

AU - Bass, Adam J

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

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U2 - 10.1158/1535-7163.MCT-17-0464

DO - 10.1158/1535-7163.MCT-17-0464

M3 - Journal article

C2 - 29654068

SN - 1535-7163

VL - 17

SP - 1526

EP - 1539

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

IS - 7

ER -

RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1-Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade

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