Department of Radiation Oncology, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China.
Department of Thoracic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, Jiangsu, China.
Cancer Gene Ther. 2024 Jul;31(7):961-969. doi: 10.1038/s41417-024-00778-4. Epub 2024 May 11.
Lung malignant tumors are a type of cancer with high incidence and mortality rates worldwide. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung malignant tumors, and most patients are diagnosed at advanced stages, leading to poor prognosis. Over the past decades, various oncogenic driver alterations associated with lung cancer have been identified, each of which can potentially serve as a therapeutic target. Rat sarcoma (RAS) genes are the most commonly mutated oncogenes in human cancers, with Kirsten rat sarcoma (KRAS) being the most common subtype. The role of KRAS oncogene in NSCLC is still not fully understood, and its impact on prognosis remains controversial. Despite the significant advancements in targeted therapy and immune checkpoint inhibitors (ICI) that have transformed the treatment landscape of advanced NSCLC in recent years, targeting KRAS (both directly and indirectly) remains challenging and is still under intensive research. In recent years, significant progress has been made in the development of targeted drugs targeting the NSCLC KRASG12C mutant subtype. However, research progress on target drugs for the more common KRASG12D subtype has been slow, and currently, no specific drugs have been approved for clinical use, and many questions remain to be answered, such as the mechanisms of resistance in this subtype of NSCLC, how to better utilize combination strategies with multiple treatment modalities, and whether KRASG12D inhibitors offer substantial efficacy in the treatment of advanced NSCLC patients.
肺恶性肿瘤是一种发病率和死亡率都很高的癌症。非小细胞肺癌（NSCLC）占所有肺恶性肿瘤的 80%以上，大多数患者在晚期被诊断出来，导致预后不良。在过去的几十年中，已经确定了与肺癌相关的各种致癌驱动基因改变，每种改变都可能成为治疗的靶点。鼠肉瘤（RAS）基因是人类癌症中最常见的突变致癌基因，其中 Kirsten 鼠肉瘤（KRAS）是最常见的亚型。KRAS 癌基因在 NSCLC 中的作用仍不完全清楚，其对预后的影响仍存在争议。尽管近年来靶向治疗和免疫检查点抑制剂（ICI）的显著进展改变了晚期 NSCLC 的治疗格局，但直接和间接靶向 KRAS 仍然具有挑战性，仍在进行深入研究。近年来，针对 NSCLC KRASG12C 突变亚型的靶向药物的开发取得了重大进展。然而，针对更为常见的 KRASG12D 亚型的靶向药物的研究进展缓慢，目前尚无特定药物被批准用于临床使用，还有许多问题亟待解答，例如这种 NSCLC 亚型的耐药机制，如何更好地利用多种治疗方式的联合策略，以及 KRASG12D 抑制剂在治疗晚期 NSCLC 患者方面是否具有显著疗效。
