Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies.
Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies.
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DOI：
10.1038/s42003-020-01552-6
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发表时间：
2021-01-04
影响因子：
5.9
通讯作者：
Martin DP
中科院分区：
文献类型：
--
作者：
Sinkala M;Nkhoma P;Mulder N;Martin DP
丝裂原活化蛋白激酶(MAPK)通路是促进正常细胞恶性转化的细胞过程的重要调节因子。导致癌症的分子异常涉及多种MAPK途径基因的突变和转录变异。在这里，我们检查了代表101种不同人类癌症的40,848例患者来源的肿瘤的基因组序列，以识别MAPK信号通路基因中与癌症相关的突变。我们发现，在ERK-1/2通路、p38通路或多个MAPK通路模块的基因内发生突变的肿瘤患者，往往比MAPK通路基因内没有突变的肿瘤患者的疾病结局更差。此外，通过整合从各种大规模分子数据集中提取的信息，我们揭示了CRISPR介导的MAPK途径基因敲除后癌细胞的适合度与其对MAPK途径抑制剂的剂量反应之间的关系。除了提供对MAPK通路的新见解外，我们还发现了特定途径基因中的漏洞，这些漏洞反映在癌细胞对MAPK靶向药物的反应中：这是一个具有指导创新疗法开发的巨大潜力的发现。Musalula Sinkala等人。报道称，总的来说，5条MAPK通路中的特定基因突变与患者的生存状况较差有关。他们在癌细胞模型中识别了在药理上易受途径抑制剂影响的基因成分，暗示了这些发现的潜在临床应用。
The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells. The molecular aberrations which lead to cancer involve mutations in, and transcription variations of, various MAPK pathway genes. Here, we examine the genome sequences of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We show that patients with tumours that have mutations within genes of the ERK-1/2 pathway, the p38 pathways, or multiple MAPK pathway modules, tend to have worse disease outcomes than patients with tumours that have no mutations within the MAPK pathways genes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the re sponses of cancer cells to MAPK targeting drugs: a revelation with great potential for guiding the development of innovative therapies. Musalula Sinkala et al. report that collectively, specific mutations of genes in 5 MAPK pathways are associated with worse patient survival. They identify gene components that are pharmacologically vulnerable to pathway inhibitors in cancer cell models, suggesting potential clinical applications of these findings.
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影响因子：
3.5
作者：
Di Giacomo S;Sollazzo M;Paglia S;Grifoni D
通讯作者：
Grifoni D
影响因子：
64.8
作者：
Claveria, Cristina;Giovinazzo, Giovanna;Torres, Miguel
通讯作者：
Torres, Miguel
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
3.3
作者：
Indini, Alice;Tondini, Carlo Alberto;Mandala, Mario
通讯作者：
Mandala, Mario