Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies.

中文翻译：

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RAS 信号转导在致癌作用、癌症治疗和耐药机制中的作用


RAS 家族的变异（HRAS、NRAS 和 KRAS）是癌症中最常见的突变之一。大约 19% 的癌症患者携带 RAS 突变，这通常与不良的临床结果有关。在过去的四十年里，KRAS 长期以来一直被认为是不可成药的靶点，因为其突变亚型中缺乏合适的小分子结合位点。然而，药物设计的最新进展使 RAS 靶向疗法变得可行，尤其是在直接KRASG12C抑制剂（如 sotorasib 和 adagrasib）获批用于治疗具有 KRASG12C 突变的非小细胞肺癌 （NSCLC） 的情况下。目前正在开发其他靶向 KRASG12D 的 KRAS 突变抑制剂用于临床，特别是用于治疗胰腺癌等高度难治性恶性肿瘤。在此，我们概述了 RAS 信号传导，进一步详细说明了 RAS 信号通路在致癌作用中的作用。这包括对人类癌症中 RAS 突变的总结，并强调治疗方法，以及各种恶性肿瘤中的新发、获得性和适应性耐药。