eIF4A inhibitors suppress cell-cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer
Files
Accepted manuscript
Supporting documentation
Date
2019-11
Authors
Kong, Tim
Xue, Yibo
Cencic, Regina
Zhu, Xianbing
Monast, Anie
Fu, Zheng
Pilon, Virginie
Sangwan, Veena
Guiot, Marie-Christine
Foulkes, William D.
Version
Accepted manuscript
OA Version
Citation
Tim Kong, Yibo Xue, Regina Cencic, Xianbing Zhu, Anie Monast, Zheng Fu, Virginie Pilon, Veena Sangwan, Marie-Christine Guiot, William D Foulkes, John A Porco, Morag Park, Jerry Pelletier, Sidong Huang. 2019. "eIF4A Inhibitors Suppress Cell-Cycle Feedback Response and Acquired Resistance to CDK4/6 Inhibition in Cancer.." Mol Cancer Ther, Volume 18, Issue 11, pp. 2158 - 2170. https://doi.org/10.1158/1535-7163.MCT-19-0162
Abstract
CDK4/6 inhibitors are FDA-approved drugs for estrogen receptor-positive (ER+) breast cancer and are being evaluated to treat other tumor types, including KRAS-mutant non-small cell lung cancer (NSCLC). However, their clinical utility is often limited by drug resistance. Here, we sought to better understand the resistant mechanisms and help devise potential strategies to overcome this challenge. We show that treatment with CDK4/6 inhibitors in both ER+ breast cancer and KRAS-mutant NSCLC cells induces feedback upregulation of cyclin D1, CDK4, and cyclin E1, mediating drug resistance. We demonstrate that rocaglates, which preferentially target translation of key cell-cycle regulators, effectively suppress this feedback upregulation induced by CDK4/6 inhibition. Consequently, combination treatment of CDK4/6 inhibitor palbociclib with the eukaryotic initiation factor (eIF) 4A inhibitor, CR-1-31-B, is synergistic in suppressing the growth of these cancer cells in vitro and in vivo Furthermore, ER+ breast cancer and KRAS-mutant NSCLC cells that acquired resistance to palbociclib after chronic drug exposure are also highly sensitive to this combination treatment strategy. Our findings reveal a novel strategy using eIF4A inhibitors to suppress cell-cycle feedback response and to overcome resistance to CDK4/6 inhibition in cancer.