KRAS突變型肺癌有望得到治療
美國哈佛醫(yī)學院Karen Cichowski研究團隊經(jīng)過不懈努力而取得一項進展。他們發(fā)現(xiàn)失控的HOX基因軸賦予KRAS突變型肺癌的表觀遺傳易感性。這一成果發(fā)表在2020年4月2日出版的《癌細胞》雜志上。
研究組報告說，一半的KRAS突變型非小細胞肺癌（NSCLC）異常表達了同源盒蛋白HOXC10，這主要是由于PRC2中未發(fā)現(xiàn)的缺陷所致，從而賦予了對異種移植和PDX模型中BET / MEK抑制劑聯(lián)合使用的敏感性。該組合的功效取決于BET抑制劑對HOXC10的抑制。
他們進一步表明，HOXC10調(diào)節(jié)敏感腫瘤中復制前復合物（pre-RC）蛋白的表達。因此，BET / MEK抑制劑抑制循環(huán)細胞中的pre-RC蛋白，觸發(fā)停滯的復制、DNA損傷和死亡。 這些研究揭示了一種針對KRAS突變型NSCLC的有前途的治療策略，可確定反應(yīng)的預(yù)測生物標志物，并定義具有可靶向表觀遺傳易感性的NSCLC的亞群。
據(jù)介紹，盡管KRAS突變在NSCLC中很常見，但缺乏有效的治療方法。
附：英文原文
Title: A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers
Author: Stephanie L. Guerra, Ophélia Maertens, Ryan Kuzmickas, Thomas De Raedt, Richard O. Adeyemi, Caroline J. Guild, Shawna Guillemette, Amanda J. Redig, Emily S. Chambers, Man Xu, Hong Tiv, Sandro Santagata, Pasi A. Jnne, Stephen J. Elledge, Karen Cichowski
Issue&Volume: 2020-04-02
Abstract: While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatmentsare lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciateddefects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograftand PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replicationcomplex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppresspre-RC proteins in cycling cells, triggering stalled replication, DNA damage, anddeath. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset ofNSCLCs with a targetable epigenetic vulnerability.
DOI: 10.1016/j.ccell.2020.03.004
Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30105-7
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