Molecular Oncology Group, Cancer Research UK Manchester Institute, the University of Manchester, Alderley Park, Manchester, UK.
Drug Discovery Unit, Cancer Research UK Manchester Institute, the University of Manchester, Alderley Park, Manchester, UK; Gene and Oncogene Targeting Team, CR-UK Cancer Therapeutics Unit, the Institute of Cancer Research, London, UK.
Ann Oncol. 2021 Feb;32(2):269-278. doi: 10.1016/j.annonc.2020.10.483. Epub 2020 Oct 29.
KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting KRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective.
The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers.
We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a KRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options.
New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.
KRAS 在大约 90%的胰腺导管腺癌、大约 35%的结直肠癌和约 20%的非小细胞肺癌中发生突变。目前在针对 KRAS 进行特异性靶向治疗方面取得了一定进展，但其他突变形式的 KRAS 的治疗选择有限，主要是因为下游信号转导和反馈机制的复杂性意味着靶向单一途径成分是无效的。
RAF 和 SRC 蛋白激酶是 KRAS 突变型胰腺导管腺癌、结直肠癌和非小细胞肺癌的经证实的治疗靶点，我们表明必须抑制这两种激酶以阻断这些癌症的生长。我们描述了 CCT3833，一种新的抑制 RAF 和 SRC 的药物，可能对 KRAS 突变型癌症有效。
我们表明，CCT3833 在体外和体内抑制 KRAS 突变型肿瘤中的 RAF 和 SRC，并且在小鼠中以可耐受的剂量抑制肿瘤生长。CCT3833 已在一项 I 期临床试验中进行评估（NCT02437227），我们在此报告它显著延长了一名对多激酶抑制剂无反应的 KRAS 梭形细胞肉瘤患者的无进展生存期，该患者对其他治疗选择有限。
新型药物 CCT3833 在 KRAS 突变型结直肠、肺和胰腺肿瘤异种移植模型中产生了显著的临床前治疗疗效，为多个临床需求未得到满足的领域提供了一种治疗选择。基于这些临床前数据和 I 期临床试验中 KRAS 突变型梭形细胞肉瘤患者的未确认缓解，CCT3833 需要在其他 KRAS 突变型癌症患者中进一步评估。
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