Theard Patricia L, Linke Amanda J, Sealover Nancy E, Daley Brianna R, Yang Johnny, Cox Katherine, Kortum Robert L
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA 20814.
bioRxiv. 2023 Jun 29:2023.01.20.524989. doi: 10.1101/2023.01.20.524989.
Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here, we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). deletion sensitized -mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term resistance assay, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by deletion; the few KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting SOS2 has the potential to eliminate the majority of osimertinib resistance.
七号缺失蛋白1和2（SOS1和SOS2）是RAS鸟嘌呤核苷酸交换因子（RasGEFs），介导生理和病理状态下依赖受体酪氨酸激酶（RTK）的RAS激活。在此，我们表明SOS2调节表皮生长因子受体（EGFR）信号阈值，以调控肺腺癌（LUAD）中EGFR酪氨酸激酶抑制剂（EGFR-TKI）奥希替尼的疗效和耐药性。SOS2缺失使携带EGFR突变的细胞对因血清减少和/或奥希替尼治疗引起的EGFR信号扰动敏感，从而抑制PI3K/AKT通路激活、致癌转化和细胞存活。PI3K/AKT信号的旁路RTK重新激活是对EGFR-TKIs的一种常见耐药机制；SOS2基因敲除减少了PI3K/AKT的重新激活，从而限制奥希替尼耐药性。在强制HGF/MET驱动的旁路模型中，SOS2基因敲除抑制了HGF刺激的PI3K信号传导，以阻断HGF驱动的奥希替尼耐药性。使用长期耐药性试验，大多数对奥希替尼耐药的培养物表现出与重新激活的RTK/AKT信号相关的混合上皮/间充质表型。相比之下，SOS2缺失显著降低了RTK/AKT依赖性奥希替尼耐药性；少数对奥希替尼耐药的SOS2基因敲除培养物主要经历了非RTK依赖性上皮-间质转化（EMT）。由于旁路RTK重新激活和/或三级EGFR突变代表了大多数奥希替尼耐药癌症，这些数据表明靶向SOS2有可能消除大多数奥希替尼耐药性。
