Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis.
Novel Calcium-Binding Ablating Mutations Induce Constitutive RET Activity and Drive Tumorigenesis.
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DOI：
10.1158/0008-5472.can-22-0834
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发表时间：
2022-10-17
期刊：
影响因子：
11.2
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中科院分区：
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对大量VUS的全面蛋白基因组学和计算机模拟分析确定了一组新的致癌突变和特征性RET癌基因中的药物突变。区分致癌突变与未知意义的变异（VUS）对于精确的癌症医学至关重要。在这里，用于阳性选择的71，756个RET变体的计算建模以及110个代表性变体的功能测定鉴定了多种人类癌症携带的三维VUS簇，这些VUS簇导致RET的钙调蛋白样基序（CaLM）中的氨基酸取代。分子动力学模拟表明，CaLM突变减少Ca 2+和周围残基之间的相互作用，并诱导含有CaLM的RET富含半胱氨酸的结构域的构象畸变。RET-CaLM突变导致RET激酶的非配体依赖性组成型激活，通过不合法的二硫键形成介导的同源二聚化。RET-CaLM突变体具有致癌和致瘤活性，可被靶向RET的酪氨酸激酶抑制剂抑制。这项研究将钙结合消融突变确定为RET的一种新型致癌突变，并表明可药用致癌基因的VUS的计算机驱动注释是一种有前途的识别靶向驱动突变的策略。对大量VUS的全面蛋白基因组学和计算机模拟分析确定了一组新的致癌突变和特征性RET癌基因中的药物突变。
Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene. Distinguishing oncogenic mutations from variants of unknown significance (VUS) is critical for precision cancer medicine. Here, computational modeling of 71,756 RET variants for positive selection together with functional assays of 110 representative variants identified a three-dimensional cluster of VUSs carried by multiple human cancers that cause amino acid substitutions in the calmodulin-like motif (CaLM) of RET. Molecular dynamics simulations indicated that CaLM mutations decrease interactions between Ca2+ and its surrounding residues and induce conformational distortion of the RET cysteine-rich domain containing the CaLM. RET-CaLM mutations caused ligand-independent constitutive activation of RET kinase by homodimerization mediated by illegitimate disulfide bond formation. RET-CaLM mutants possessed oncogenic and tumorigenic activities that could be suppressed by tyrosine kinase inhibitors targeting RET. This study identifies calcium-binding ablating mutations as a novel type of oncogenic mutation of RET and indicates that in silico–driven annotation of VUSs of druggable oncogenes is a promising strategy to identify targetable driver mutations. Comprehensive proteogenomic and in silico analyses of a vast number of VUSs identify a novel set of oncogenic and druggable mutations in the well-characterized RET oncogene.