Désage Anne-Laure, Léonce Camille, Swalduz Aurélie, Ortiz-Cuaran Sandra
Univ Lyon, Claude Bernard Lyon 1 University, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Lyon, France.
Department of Pulmonology and Thoracic Oncology, North Hospital, University Hospital of Saint-Etienne, Saint-Etienne, France.
Front Oncol. 2022 Feb 16;12:796832. doi: 10.3389/fonc.2022.796832. eCollection 2022.
Although activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit failed in the past decade. mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (, adagrasib, sotorasib) that target specifically in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting and promising approaches of combined therapy to overcome acquired resistance to inhibitors.
尽管激活突变是非小细胞肺癌（NSCLC）中最常见的致癌驱动因素，但在过去十年中，各种抑制该突变的尝试均告失败。该突变与预后不良以及对标准治疗方案反应不佳相关。最近开发的新型治疗药物（如阿达格拉西布、索托拉西布），它们特异性靶向处于GDP结合状态的该突变，已证明在治疗这一亚组患者方面取得了前所未有的成功。尽管这些药物具有临床前和临床疗效，但已有报道称存在几种对该突变抑制剂获得性耐药的机制。在这种情况下，包括抑制SHP2、SOS1或该突变下游效应器的联合治疗策略，似乎对于克服获得性耐药特别有意义。在本综述中，我们将讨论针对该突变的新型治疗策略以及克服对该突变抑制剂获得性耐药的联合治疗的前景方法。
