eIF4A inhibitors suppress cell cycle feedback response and acquired resistance to CDK4/6 inhibition in cancer
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 of CDK4/6 inhibitors in both ER+ breast cancer and KRAS mutant NSCLC cells induce 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 suppresses 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 sup...Continue Reading
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