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Mol Cancer Ther. 2019 Nov;18(11):2158-2170. doi: 10.1158/1535-7163.MCT-19-0162. Epub 2019 Aug 8.

eIF4A Inhibitors Suppress Cell-Cycle Feedback Response and Acquired Resistance to CDK4/6 Inhibition in Cancer.

Author information

1
Department of Biochemistry, The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
2
Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, Quebec, Canada.
3
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
4
Department of Medical Genetics, and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
5
Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
6
Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, Massachusetts.
7
Department of Biochemistry, The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. sidong.huang@mcgill.ca.

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.

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