Research and Development, Scorpion Therapeutics, Boston, Massachusetts.
Department of Biology, Scorpion Therapeutics, South San Francisco, California.
Cancer Discov. 2023 Nov 1;13(11):2432-2447. doi: 10.1158/2159-8290.CD-23-0396.
Phosphoinositide 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.
磷酸肌醇 3-激酶 α（PIK3CA）是癌症中突变最多的基因之一，尤其是在乳腺癌、妇科癌和头颈部鳞状细胞癌肿瘤中。突变发生在整个基因中，但螺旋和激酶结构域中的热点突变占主导地位。阿培利司（alpelisib）的出现确立了同工型选择性 PI3Kα 抑制的治疗益处，该药物对野生型和突变酶均具有等效的活性。野生型 PI3Kα 的抑制与严重的高血糖和皮疹有关，这限制了阿培利司的使用，并表明选择性靶向突变 PI3Kα 可能降低毒性并提高疗效。在这里，我们描述了 STX-478，一种变构 PI3Kα 抑制剂，可选择性靶向常见的 PI3Kα 螺旋和激酶结构域突变肿瘤。STX-478 在人肿瘤异种移植模型中表现出强大的疗效，而不会引起阿培利司观察到的代谢功能障碍。将 STX-478 与氟维司群和/或细胞周期蛋白依赖性激酶 4/6 抑制剂联合使用具有良好的耐受性，并在 ER+HER2-异种移植肿瘤模型中提供了强大且持久的肿瘤消退。
这些临床前数据表明，突变选择性、变构 PI3Kα 抑制剂 STX-478 提供了强大的疗效，同时避免了与非选择性抑制剂阿培利司相关的代谢功能障碍。我们的结果支持 STX-478 在 PI3Kα 突变癌症中的临床评估，这有望扩大治疗窗口并减轻代偿性胰岛素释放。请参阅 Kearney 和 Vasan 的相关评论，第 2313 页。本文选自本期精选文章，第 2293 页。
