Oncogene-induced senescence and senescence-associated secretory phenotype (SASP) determine the efficacy of palbociclib in PIK3CA mutated colorectal cancer

Palbociclib is an excellent CDK4/6 inhibitor, but its clinical application is mainly limited to the treatment of advanced ER + /HR + and HER2 − breast cancer. Its efficacy in colorectal cancer (CRC) is evaluated in multiple trials and so far remains undetermined. We found that the PIK3CA-mutant CRC cells were insensitive to palbociclib treatment compared with the PIK3CA wild-type counterparts, and they were in an OIS (oncogene-induced senescence) state which was predisposed to a strong senescence-associated secretory phenotype (SASP) upon treatment. These senescent cells excessively secreted various SASP factors LCN2, and ultimately caused palbociclib-resistance via upregulation of EGFR in the non-senescent CRC cells. Importantly, a drug combination screen identified that erlotinib could synergize with palbociclib to overcome the SASP-induced resistance. Overall, we found that PIK3CA mutation-induced senescence compromised the efficacy of palbociclib treatment in CRC but co-targeting EGFR could minimize the OIS-associated side effects while preserving the beneficial effects.