Assessment of STX-478 mutant selectivity by profiling target engagement and functional activity in cellular assays. A, pAKT inhibition dose–response curves (HTRF assay) in MCF10A isogenic cell lines. B, Representative pAKT inhibition dose–response curves (HTRF assay). C, Correlation plot comparing alpelisib and STX-478 potency (pAKT HTRF assay) in a panel of kinase-domain mutant cell lines (orange dots) and WT PI3Kα SKBR3 (black dots) described in Supplementary Table S1. D, Correlation plot of alpelisib and STX-478 comparing pAKT IC50 at 1 hour and viability [CellTiter-Glo (CTGlo)] GI50 at 72 hours across the indicated panel of cell lines. E, Sensitivity of cancer cell lines to STX-478 and alpelisib grouped by cancer type and PIK3CA and PTEN mutational status. Screening was performed by the Broad Institute using the PRISM platform. F, Two-hour glucose uptake in primary human adipocytes as indicated in the bar graph (percent vehicle response). Seventy-two-hour viability data in H1047R PI3Kα-mutant T47D cell line are overlaid in the orange dose–response curve for comparison.
ARTICLE ABSTRACTPhosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2− xenograft tumor models.
These preclinical data demonstrate that the mutant-selective, allosteric PI3Kα inhibitor STX-478 provides robust efficacy while avoiding the metabolic dysfunction associated with the nonselective inhibitor alpelisib. Our results support the ongoing clinical evaluation of STX-478 in PI3Kα-mutated cancers, which is expected to expand the therapeutic window and mitigate counterregulatory insulin release.See related commentary by Kearney and Vasan, p. 2313.This article is featured in Selected Articles from This Issue, p. 2293