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

Cao, P.; Zhou, X.; Yang, S.; Shen, T.; Wang, S.; Yu, H.; Liu, X.; Gong, Y.; Wang, W.; Wang, H.; Zhou, T.; Wang, J.; Fan, Z.; Huang, M.; Qian, X.; Wang, X.; Wang, Q.; Yang, L.; Zhang, Y.; Lin, F.

doi:10.1101/2024.11.15.623304

bioRxiv · 10.1101/2024.11.15.623304

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

Cao, P.·Zhou, X.·Yang, S.·Shen, T.·Wang, S.·Yu, H.·Liu, X.·Gong, Y.·Wang, W.·Wang, H.·Zhou, T.·Wang, J.·Fan, Z.·Huang, M.·Qian, X.·Wang, X.·Wang, Q.·Yang, L.·Zhang, Y.·Lin, F.

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Abstract

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.

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Cao, P., Zhou, X., Yang, S., Shen, T., Wang, S., Yu, H., Liu, X., Gong, Y., Wang, W., Wang, H., Zhou, T., Wang, J., Fan, Z., Huang, M., Qian, X., Wang, X., Wang, Q., Yang, L., Zhang, Y., Lin, F.. 2024-11-18. Oncogene-induced senescence and senescence-associated secretory phenotype (SASP) determine the efficacy of palbociclib in PIK3CA mutated colorectal cancer. https://doi.org/10.1101/2024.11.15.623304

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