小柯机器人

美国纽约大学Kwok-Kin Wong等研究人员合作发现，KMT2D缺陷驱动肺鳞状细胞癌和对RTK-RAS抑制的超敏反应。该研究于2022年12月15日在线发表于国际一流学术期刊《癌细胞》。

Title: KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

Author: Yuanwang Pan, Han Han, Hai Hu, Hua Wang, Yueqiang Song, Yuan Hao, Xinyuan Tong, Ayushi S. Patel, Selim Misirlioglu, Sittinon Tang, Hsin-Yi Huang, Ke Geng, Ting Chen, Angeliki Karatza, Fiona Sherman, Kristen E. Labbe, Fan Yang, Alison Chafitz, Chengwei Peng, Chenchen Guo, Andre L. Moreira, Vamsidhar Velcheti, Sally C.M. Lau, Pengfei Sui, Haiquan Chen, J. Alan Diehl, Anil K. Rustgi, Adam J. Bass, John T. Poirier, Xiaoyang Zhang, Hongbin Ji, Hua Zhang, Kwok-Kin Wong

Issue&Volume: 2022-12-15

Abstract: Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer withlimited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSConcogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesiswherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partlythrough reprogramming the chromatin landscape to repress the expression of proteintyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RASsignaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibitslung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSConcogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

DOI: 10.1016/j.ccell.2022.11.015

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00562-1

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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