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

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.

Cell Cycle and Beyond: Exploiting New RB1 Controlled Mechanisms for Cancer Therapy

“…It now appears that in many tumor contexts, there exist parallel or adaptive pathways that allow for cell cycle progression in spite of pharmacological CDK4/6 inhibition ( Figure 2). Multiple studies over the last year have begun to shed-light on this "dark-side" of the cell cycle, where other CDK complexes compensate for the pharmaceutical suppression of CDK4/6 and limit therapeutic efficacy [31][32][33][34]. These finding are congruent with prior observations indicating cells can divide in the genetic absence of CDK4 and 6 activity and clearly illustrate the involvement of compensatory pathways [35].…”

Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

“…These data showed that CDK4/6 inhibition had no effect related to canonical signaling through ERK, AKT, or MTOR pathways as determined by phosphorylation of ERK, AKT and S6 respectively (Fig S1). However, the treatment with trametinib resulted in expected suppression of ERK activity and in several models also suppressed activity through the MTOR and AKT pathways (Fig S1), as has been recently reported in other RAS-driven tumors 17 . To determine the features of therapeutic cooperation, we interrogated canonical determinants of cell cycle control.…”

“…Interestingly, in preclinical studies PDAC models are surprisingly resistant to CDK4/6 inhibition 14, 15 . However, combination with MTOR or MEK inhibitors have been reported to enhance response to CDK4/6 inhibition in PDAC and other RAS-driven tumor types 15-17 . In spite of the potency of such combinations in enforcing cell cycle withdrawal, tumor cells continue to survive and as a result acquired resistance represents a significant challenge with such cytostatic combinations.…”

Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38

“…The role of the CDK4/cyclin D-Rb axis on cell size regulation has been purported by studies from our lab and others (Ginzberg et al, 2018;Schmoller et al, 2015;. While the mechanisms by which CDK4 activity sets target size remains to be investigated, there is increasing evidence that inhibition of CDK4 activity results in increased biosynthetic capacity, such as mitochondrial size and activity, presumably through its feedback on mTORC1 signaling (Cretella et al, 2018;Franco et al, 2016;Haines et al, 2018;Jansen et al, 2017;Romero-Pozuelo et al, 2020).…”