Here, we demonstrate that the initial efficacy of palbociclib in both in vitro and in vivo models of KRAS-mutant NSCLC is complicated by the rapid onset of acquired resistance, mediated by increased expression of CDK6, cyclin D1, cyclin D3 and cyclin E. Additionally, we establish the importance of increased ERK1/2 activity in palbociclib-resistant cells that mediates D-cyclin and CDK6 expression; ERK activity is controlled upstream in part by FGFR1 and exerts its effects through mTOR activation. Here, MAPK3 is linked to non-small cell lung carcinoma.