Priority Research Papers:

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

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

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Press Release

Oncotarget. 2018; 9:31572-31589. https://doi.org/10.18632/oncotarget.25803

Metrics: PDF 2297 views  |   HTML 6565 views  |   ?  


Eric Haines1, Ting Chen1,3, Naveen Kommajosyula1, Zhao Chen1,4, Grit S. Herter-Sprie1,5, Liam Cornell1, Kwok-Kin Wong1,2,3 and Geoffrey I. Shapiro1,2

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

2 Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

3 Perlmutter Cancer Center, New York University, Langone Medical Center, New York, NY, USA

4 Novartis Institutes for BioMedical Research, Cambridge, MA, USA

5 University Hospital of Cologne, Weyertal, Cologne, Germany

Correspondence to:

Geoffrey I. Shapiro, email: [email protected]

Keywords: CDK4/6 inhibitor; MEK inhibitor; FGFR1; KRAS-mutant non-small cell lung cancer; drug resistance

Received: September 03, 2017    Accepted: July 08, 2018    Published: August 03, 2018


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 25803