MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer

Purpose: Loss of cell cycle control is a hallmark of cancer, which can be targeted with agents, including Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1-S cell cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types, and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon.  Experimental Design: In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer.  Results: This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phospho-proteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and pro-metastatic signaling. However, CDK4/6 inhibitor resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. Conclusions: In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer.