Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2024 Feb 16;30(4):655-662. doi: 10.1158/1078-0432.CCR-23-2098.
KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent in vitro and in vivo antitumor efficacy against KRASG12D-mutant cancer cells, especially in PDAC, leading to its recent initiation of a phase I/II clinical trial. Here, we provide a summary of the recent advancements related to the use of MRTX1133 for treating KRASG12D-mutant PDAC, focusing on its efficacy and underlying mechanistic actions. In addition, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bringing about a paradigm shift in its management.
KRAS 突变驱动着许多癌症中的致癌改变，尤其是在人类胰腺导管腺癌（PDAC）中。大约 93%的 PDAC 存在 KRAS 突变，其中 G12D（约 42%的病例）和 G12V（约 32%的病例）最为常见。最近，sotorasib（AMG510）获批用于治疗非小细胞肺癌患者，这是 KRAS 靶向治疗的一个突破，sotorasib 是一种小分子、共价、选择性 KRASG12C 抑制剂。然而，仍需要开发其他急需的 KRAS 突变抑制剂来治疗 PDAC。值得注意的是，Mirati Therapeutics 最近通过广泛的基于结构的药物设计开发了 MRTX1133，这是一种小分子、非共价、选择性 KRASG12D 抑制剂。MRTX1133 在体外和体内对 KRASG12D 突变的癌细胞均显示出强大的抗肿瘤疗效，尤其是在 PDAC 中，这导致其最近启动了一项 I/II 期临床试验。在这里，我们提供了关于使用 MRTX1133 治疗 KRASG12D 突变型 PDAC 的最新进展的概述，重点介绍其疗效和潜在的作用机制。此外，我们还讨论了 MRTX1133 治疗 PDAC 的潜在挑战和未来方向，包括克服内在和获得性耐药性、开发有效的联合疗法以及提高 MRTX1133 的口服生物利用度和靶谱。临床前研究取得的有希望的结果表明，MRTX1133 可能会彻底改变 PDAC 的治疗方法，带来管理上的范式转变。
