Oncogene induced senescence and senescence-associated secretory phenotype (SASP) determines the efficacy of palbociclib in PIK3CA mutated colorectal cancer
Palbociclib, a classic CDK4/6 inhibitor, has been extensively studied in the context of targeted cancer therapy. We have systematically investigated the applicability of palbociclib in colorectal cancer, utilizing high-throughput sequencing and other methods to explore its resistance mechanisms. Our findings reveal that PIK3CA gene mutations promote a palbociclib-induced senescent phenotype and alter the expression profile of SASP factors. Among these, the SASP factor LCN2 contributes to cellular tolerance to palbociclib by upregulating EGFR protein expression. In summary, our sequencing data provide a molecular framework for the relationship between PIK3CA gene mutations and both palbociclib-induced cellular senescence and resistance. Overall design: To investigate the role of PIK3CA gene mutations in resistance to palbociclib, we created isogenic cell lines harboring PIK3CA mutations (E545K and H1047R) in the wild-type LOVO cell line using lentiviral vectors. These mutant cell lines were named E545K (2# and 5#) and H1047R (2# and 3#). We then treated both the wild-type and mutant cell lines, E545K (2#) and H1047R (3#), with palbociclib to induce senescence and conducted transcriptome sequencing. Furthermore, we treated cells with conditioned medium containing senescence-associated secretory phenotype (SASP) factors to explore their function through transcriptome sequencing. In-depth, we studied the therapeutic mechanism by treating the PIK3CA mutant cell lines with a combination of palbociclib and erlotinib.