PIK3CA is one of the most frequently mutated oncogenes; the p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting the PI3K p110a catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with PIK3CA -mutant breast cancer. However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer. Significance: The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wild-type p110a protein may result in improved therapeutic index in PIK3CA -mutant tumors. See related commentary by Vanhaesebroeck et al., [p. 20][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/12/20?iss=1 [2]: /lookup/volpage/12/1?iss=1

中文翻译：

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突变体 PI3K{alpha} 的 RTK 依赖性诱导降解提高了 GDC-0077 (Inavolisib) 的功效

PIK3CA 是最常见突变的癌基因之一；它编码的 p110a 蛋白在肿瘤细胞增殖中发挥着核心作用。针对 PI3K p110a 催化亚基的小分子抑制剂已进入临床试验，早期 GDC-0077 研究显示对 PIK3CA 突变乳腺癌患者具有抗肿瘤活性和可控的安全性。然而，临床前研究表明，PI3K 通路抑制会释放负反馈并激活受体酪氨酸激酶信号传导，重新参与该通路并减弱药物活性。在这里，我们发现 GDC-0077 和 taselisib 通过独特的 HER2 依赖性突变体 p110a 降解更有效地抑制突变体 PI3K 通路信号传导和细胞活力。两者在维持长期通路抑制方面比其他 PI3K 抑制剂更有效。这项研究建立了一种新策略，通过选择性降解突变癌蛋白来识别特异性靶向突变肿瘤的抑制剂，并为在 HER2 阳性乳腺癌患者中寻找 PI3Kα 降解剂提供了强有力的理由。意义：PI3K抑制剂GDC-0077和taselisib具有独特的作用机制；两种抑制剂都会导致突变 p110a 蛋白的降解。能够触发突变型p110a特异性降解而不显着改变野生型p110a蛋白的抑制剂可能导致PIK3CA突变型肿瘤的治疗指数提高。参见 Vanhaesebroeck 等人的相关评论，[p. 11]。20][1]。本文在本期专题中突出显示，[p. 11]。1][2] [1]: /lookup/volpage/12/20?iss=1 [2]: /lookup/volpage/12/1?iss=1