Han Chang Woo, Jeong Mi Suk, Ha Sung Chul, Jang Se Bok
Department of Molecular Biology, College of Natural Sciences, Pusan National University, 2, Busandaehak-ro 63 beon-gil, Geumjeong-gu, Busan 46241, Korea.
. Korea Nanobiotechnology Center, Pusan National University, 2, Busandaehak-ro 63 beon-gil, Geumjeong-gu, Busan 46241, Korea.
Cancers (Basel). 2020 May 30;12(6):1412. doi: 10.3390/cancers12061412.
Kirsten-RAS (KRAS) has been the target of drugs because it is the most mutated gene in human cancers. Because of the low affinity of drugs for KRAS mutations, it was difficult to target these tumor genes directly. We found a direct interaction between KRAS G12V and tumor suppressor novel H-REV107 peptide with high binding affinity. We report the first crystal structure of an oncogenic mutant, KRAS G12V-H-REV107. This peptide was shown to interact with KRAS G12V in the guanosine diphosphate (GDP)-bound inactive state and to form a stable complex, blocking the activation function of KRAS. We showed that the peptide acted as an inhibitor of mutant KRAS targets by [α-P] guanosine triphosphate (GTP) binding assay. The H-REV107 peptide inhibited pancreatic cancer and colon cancer cell lines in cell proliferation assay. Specially, the H-REV107 peptide can suppress pancreatic tumor growth by reduction of tumor volume and weight in xenotransplantation mouse models. Overall, the results presented herein will facilitate development of novel drugs for inhibition of KRAS mutations in cancer patients.
Kirsten原癌基因RAS（KRAS）一直是药物作用的靶点，因为它是人类癌症中突变最多的基因。由于药物对KRAS突变体的亲和力较低，直接靶向这些肿瘤基因具有一定难度。我们发现KRAS G12V与肿瘤抑制因子新型H-REV107肽之间存在直接相互作用，且结合亲和力较高。我们报道了致癌突变体KRAS G12V-H-REV107的首个晶体结构。该肽在结合二磷酸鸟苷（GDP）的无活性状态下与KRAS G12V相互作用，并形成稳定复合物，从而阻断KRAS的激活功能。通过[α-P]三磷酸鸟苷（GTP）结合试验，我们证明该肽可作为突变型KRAS靶点的抑制剂。在细胞增殖试验中，H-REV107肽抑制了胰腺癌细胞系和结肠癌细胞系的生长。特别地，在异种移植小鼠模型中，H-REV107肽可通过减小肿瘤体积和重量来抑制胰腺肿瘤生长。总体而言，本文所呈现的结果将有助于开发用于抑制癌症患者KRAS突变的新型药物。
