Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway in KRAS -mutant non-small cell lung cancer

Oncotarget
Eric HainesGeoffrey I Shapiro

Abstract

CDK4 is emerging as a target in KRAS-mutant non-small cell lung cancer (NSCLC). We demonstrate that KRAS-mutant NSCLC cell lines are initially sensitive to the CDK4/6 inhibitor palbociclib, but readily acquire resistance associated with increased expression of CDK6, D-type cyclins and cyclin E. Resistant cells also demonstrated increased ERK1/2 activity and sensitivity to MEK and ERK inhibitors. Moreover, MEK inhibition reduced the expression and activity of cell cycle proteins mediating palbociclib resistance. In resistant cells, ERK activated mTOR, driven in part by upstream FGFR1 signaling resulting from the extracellular secretion of FGF ligands. A genetically-engineered mouse model of KRAS-mutant NSCLC initially sensitive to palbociclib similarly developed acquired resistance with increased expression of cell cycle mediators, ERK1/2 and FGFR1. In this model, resistance was delayed with combined palbociclib and MEK inhibitor treatment. These findings implicate an FGFR1-MAP kinase-mTOR pathway resulting in increased expression of D-cyclins and CDK6 that confers palbociclib resistance and indicate that CDK4/6 inhibition acts to promote MAP kinase dependence.

References

Aug 23, 1996·The Journal of Biological Chemistry·J N LavoieJ Pouysségur
May 9, 1997·The Journal of Biological Chemistry·T Zarkowska, S Mittnacht
Jul 1, 1999·Genes & Development·C J Sherr, J M Roberts
Jun 6, 2003·Oncogene·Kishalay HoareW Stratford May
Aug 7, 2007·Nature·Hongbin JiKwok-Kin Wong
Oct 28, 2008·Bioorganic & Medicinal Chemistry Letters·Stephen D BarrettHaile Tecle
Jul 1, 2009·Molecular and Cellular Biology·Kelly A McClellanRuth S Slack
Nov 26, 2009·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Charles A ButtsFrances A Shepherd
Dec 22, 2009·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Chen MaoQing Chen
Mar 25, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Eric B HauraShirish M Gadgeel
Jun 26, 2013·The American Journal of Pathology·Richard G Pestell
Jun 24, 2014·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Cheng-Yi WangKuen-Feng Chen
Jan 6, 2015·Oncotarget·Barbie Taylor-HardingW Ruprecht Wiedemeyer
Apr 22, 2015·The Journal of Biological Chemistry·Gaofeng FanNicholas K Tonks
Sep 16, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Elizabeth K ZiemkeJudith S Sebolt-Leopold
Dec 15, 2015·Cancer Discovery·Charles J SherrGeoffrey I Shapiro
Jan 6, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Zhen TaoBo Lu
Mar 30, 2016·Cancer Research·Maria Teresa Herrera-AbreuVioleta Serra
Jun 25, 2016·Nature·Eusebio ManchadoScott W Lowe
Nov 4, 2016·Nature Reviews. Drug Discovery·Jonathan M L Ostrem, Kevan M Shokat
Oct 13, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lori S HartJohn M Maris
Sep 1, 2017·Nature Communications·Marta KovatchevaAndrew Koff
Dec 14, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·R CondorelliA Bardia
Jan 10, 2018·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Chellappagounder ThangavelRobert B Den

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Citations

Dec 14, 2019·Science·Charles J Sherr
Feb 19, 2019·Oncotarget·Jose Pacheco, Erin Schenk
Apr 5, 2019·Cell Proliferation·Xiaodiao KangZhi-Wei Wang
Jun 7, 2020·Acta Pharmacologica Sinica·Xia-Qing XuLing Ding
Apr 4, 2021·International Journal of Molecular Sciences·Jens Köhler, Pasi A Jänne
Jun 10, 2021·Expert Reviews in Molecular Medicine·Marika A V Reinius, Elizabeth Smyth
Jun 29, 2021·Expert Review of Anticancer Therapy·Komal JhaveriGeoffrey I Shapiro
Aug 12, 2021·Molecular Cancer Therapeutics·Kelsey W NassarRebecca E Schweppe
Oct 17, 2021·Cell Death & Disease·Gian Luca Rampioni VinciguerraGustavo Baldassarre
Jan 14, 2022·Science·Anne FasslPiotr Sicinski

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Methods Mentioned

BETA
flow cytometry
Co-immunoprecipitation
immunoprecipitation
protein assay

Clinical Trials Mentioned

NCT02022982
NCT02703571

Software Mentioned

Modfit
CellQuest

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