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 G 1 –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 phosphoproteomics 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 prometastatic 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.
Bibliographical noteFunding Information:
This study was funded by the NIH R01CA176401 (K.E. Knudsen), R01CA217329 (K.E. Knudsen and W.K. Kelly), Prostate Cancer Foundation Young Investigator Awards (R. de Leeuw: Marjorie Katz Foundation 2016, J.M. Drake: 2015), Prostate Cancer Foundation Challenge Award (W.K. Kelly and K.E. Knudsen), Novartis (J.A. Diehl and K.E. Knudsen), R01CA093237 (J.A. Diehl), National Institute of General Medical Sciences of the NIH T32 GM008339 (L.C. Cheng), Department of Defense Prostate Cancer Research Program W81XWH-15-1-0236 (J.M. Drake), New Jersey Health Foundation grant (J.M. Drake), and Sidney Kimmel Cancer Center Shared Resources (5P30CA056036-17).
© 2018 American Association for Cancer Research.