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

Eric Haines,Liam Cornell,Ting Chen,Kwok-Kin Wong,Geoffrey I Shapiro,Grit S Herter-Sprie,Naveen Kommajosyula,Zhao Chen

doi:10.18632/oncotarget.25803

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.

Highlights

KRAS mutations occur in approximately 1530% of non-small cell lung cancers (NSCLCs) [1]
We demonstrate that KRAS-mutant NSCLC cell lines are initially sensitive to the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor palbociclib, but readily acquire resistance associated with increased expression of CDK6, D-type cyclins and cyclin E
These findings implicate an fibroblast growth factor receptor 1 (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

Summary

Introduction

KRAS mutations occur in approximately 1530% of non-small cell lung cancers (NSCLCs) [1]. These mutations are associated with a poor response to chemotherapeutics and EGFR targeted therapies, and an overall shortened survival across disease stages [2,3,4,5]. The development of effective strategies for this lung cancer subset remains a critical unmet medical need. Pharmacological targeting of KRAS is being investigated [6], the majority of efforts have focused on the inhibition of downstream components of KRAS-driven pathways. Preclinical modeling has suggested the dominance of the mitogen-activated protein kinase (MAPK) pathway in KRAS-driven cancers, translating to trials of MEK inhibition [7]. MEK inhibitors have shown limited clinical success either as monotherapy or in combination with chemotherapy [8, 9]

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Conclusion