Khan Sajid, Wiegand Janet, Zhang Peiyi, Hu Wanyi, Thummuri Dinesh, Budamagunta Vivekananda, Hua Nan, Jin Lingtao, Allegra Carmen J, Kopetz Scott E, Zajac-Kaye Maria, Kaye Frederic J, Zheng Guangrong, Zhou Daohong
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.
J Hematol Oncol. 2022 Mar 9;15(1):23. doi: 10.1186/s13045-022-01241-3.
KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRAS, was recently approved for the treatment of KRAS-mutated non-small cell lung cancer (NSCLC). However, the efficacy of sotorasib and other KRAS inhibitors is limited by intrinsic resistance in colorectal cancer (CRC) and by the rapid emergence of acquired resistance in all treated tumors. Therefore, there is an urgent need to develop novel combination therapies to overcome sotorasib resistance and to maximize its efficacy. We assessed the effect of sotorasib alone or in combination with DT2216 (a clinical-stage BCL-X proteolysis targeting chimera [PROTAC]) on KRAS-mutated NSCLC, CRC and pancreatic cancer (PC) cell lines using MTS cell viability, colony formation and Annexin-V/PI apoptosis assays. Furthermore, the therapeutic efficacy of sotorasib alone and in combination with DT2216 was evaluated in vivo using different tumor xenograft models. We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRAS tumor cell lines that partially responded to sotorasib treatment. Mechanistically, sotorasib treatment led to stabilization of BIM and co-treatment with DT2216 inhibited sotorasib-induced BCL-X/BIM interaction leading to enhanced apoptosis in KRAS tumor cell lines. Furthermore, DT2216 co-treatment significantly improved the antitumor efficacy of sotorasib in vivo. Collectively, our findings suggest that due to cytostatic activity, the efficacy of sotorasib is limited, and therefore, its combination with a pro-apoptotic agent, i.e., DT2216, shows synergistic responses and can potentially overcome resistance.
KRAS突变是最常见的致癌驱动因素。索托拉西布（AMG510）是一种KRAS共价抑制剂，最近被批准用于治疗KRAS突变的非小细胞肺癌（NSCLC）。然而，索托拉西布和其他KRAS抑制剂的疗效受到结直肠癌（CRC）的内在耐药性以及所有治疗肿瘤中快速出现的获得性耐药性的限制。因此，迫切需要开发新的联合疗法来克服索托拉西布耐药性并最大化其疗效。我们使用MTS细胞活力、集落形成和Annexin-V/PI凋亡试验，评估了索托拉西布单独使用或与DT2216（一种临床阶段的BCL-X蛋白水解靶向嵌合体[PROTAC]）联合使用对KRAS突变的NSCLC、CRC和胰腺癌（PC）细胞系的影响。此外，使用不同的肿瘤异种移植模型在体内评估了索托拉西布单独使用和与DT2216联合使用的治疗效果。我们观察到单独使用索托拉西布时反应存在异质性，而其与DT2216联合使用则强烈抑制了对索托拉西布治疗部分有反应的KRAS肿瘤细胞系的活力。从机制上讲，索托拉西布治疗导致BIM稳定，与DT2216共同治疗抑制了索托拉西布诱导的BCL-X/BIM相互作用，从而导致KRAS肿瘤细胞系凋亡增强。此外，DT2216共同治疗显著提高了索托拉西布在体内的抗肿瘤疗效。总体而言，我们的研究结果表明，由于细胞生长抑制活性，索托拉西布的疗效有限，因此，其与促凋亡剂DT2216联合使用显示出协同反应，并有可能克服耐药性。
