Simultaneous inhibition of PI3Kα and EZH1/2 suppresses PIK3CA helical domain mutated CRC by promoting IL15-mediated activation of NK cells

The PIK3CA gene encodes p110α, the catalytic subunit of phosphoinositide 3-kinase (PI3K), and is among the most frequently mutated oncogenes in multiple cancers, including breast and colorectal cancer (CRC) 1 . Two FDA-approved PI3Kα-specific inhibitors, Alpelisib and Inavolisib, are currently used in combination with fulvestrant to treat hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–), PIK3CA-mutated breast cancer. However, extending PI3Kα-targeted therapy to PIK3CA-mutant CRC requires new and effective combination strategies. Most oncogenic PIK3CA/p110α mutations cluster in two hotspot regions: the helical domain and the kinase domain. Approximately half of all p110α mutations arise in the helical domain, with E545K being the most common recurrent alteration 1 . Our previous work demonstrated that helical-domain mutant p110α aberrantly interacts with insulin receptor substrate 1 (IRS1) while losing its interaction with the regulatory subunit p85β 2 . The disengaged p85β subsequently translocates to the nucleus and stabilizes EZH1/2 3 . We further showed that combining Alpelisib with the EZH1/2 inhibitor Tazemetostat induces regression of xenograft tumors harboring a helical-domain PIK3CA mutation 3 . Here, we report that the combination of Alpelisib and Tazemetostat additively upregulates interleukin-15 (IL15) expression in helical-domain mutant CRC, leading to activation of natural killer (NK) cells, which in turn contributes to robust CRC tumor suppression.