An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.
An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy.
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DOI：
10.1186/s12885-022-09344-3
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发表时间：
2022-03-10
期刊：
影响因子：
3.8
通讯作者：
Yeatman TJ
中科院分区：
文献类型：
--
作者：
Yang M;Davis TB;Pflieger L;Nebozhyn MV;Loboda A;Wang H;Schell MJ;Thota R;Pledger WJ;Yeatman TJ
超过一半的结直肠癌（CRCs）与RAS/RAF/MEK/ERK通路的致癌信号传导存在固有联系。然而，靶向治疗抑制剂的前景因令人失望的临床效果而受挫，这可能是由于复杂的耐药机制尚未被充分理解。本研究旨在探究MEK抑制剂相关的耐药信号传导，并确定可能对生物标志物驱动的药物组合敏感的结直肠癌患者亚群。
我们根据共识分子亚型（CMS）对2250例原发性和转移性人类结直肠癌肿瘤进行分类。对于每个肿瘤，我们生成了多个基因表达特征评分，用于衡量MEK通路激活、MEKi“旁路”耐药、SRC激活、达沙替尼敏感性、上皮 - 间质转化（EMT）、PC1、人Lgr5 - 肠道干细胞（Hu - Lgr5 - ISC）、人EphB2 - 肠道干细胞（Hu - EphB2 - ISC）、人晚期TA（Hu - Late TA）、人增殖（Hu - Proliferation）以及WNT活性。我们进行了相关性、生存分析和其他生物信息学分析。在两个独立的公开可用的结直肠癌肿瘤数据集（n = 585和n = 677）以及一个结直肠癌细胞系数据集（n = 154）中进行了验证分析。
在此我们报道了SRC在介导对MEK抑制（MEKi）的“旁路”耐药中起核心作用，主要是在癌症干细胞（CSCs）中。我们对2250例结直肠癌肿瘤进行的综合全面的基因表达特征分析显示，MEKi耐药与SRC激活显著相关（斯皮尔曼P < 10⁻³²⁰），SRC激活同样与上皮 - 间质转化（EMT）、局部转移以及预后不良的疾病复发相关。更深入的分析表明，MEKi耐药和SRC激活都优先与间充质癌症干细胞表型相关。这种相关性在其他独立的结直肠癌肿瘤和细胞系数据集中得到了验证。CMS分类分析表明CMS1 - 4亚型与MEKi耐药和SRC激活之间存在显著不同的关联。重要的是，预计MEKi + SRCi敏感性主要出现在KRAS突变的、具有间充质癌症干细胞样的CMS4结直肠癌中。
代表结直肠癌异质性的大型人类肿瘤基因表达数据集能够提供迄今为止细胞系模型无法提供的深刻生物学见解，提示了新的重新利用的药物组合。我们确定SRC是间充质干细胞样结直肠癌中MEKi靶向治疗相关耐药的一个常见可靶向节点——一个致命弱点，这可能有助于开发一种生物标志物驱动的药物组合（MEKi + SRCi）来治疗有问题的结直肠癌亚群。
在线版本包含补充材料，可在10.1186/s12885 - 022 - 09344 - 3获取。
Over half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s). We classified 2250 primary and metastatic human CRC tumors by consensus molecular subtypes (CMS). For each tumor, we generated multiple gene expression signature scores measuring MEK pathway activation, MEKi “bypass” resistance, SRC activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late TA, Hu-Proliferation, and WNT activity. We carried out correlation, survival and other bioinformatic analyses. Validation analyses were performed in two independent publicly available CRC tumor datasets (n = 585 and n = 677) and a CRC cell line dataset (n = 154). Here we report a central role of SRC in mediating “bypass”-resistance to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated and comprehensive gene expression signature analyses in 2250 CRC tumors reveal that MEKi-resistance is strikingly-correlated with SRC activation (Spearman P < 10–320), which is similarly associated with EMT (epithelial to mesenchymal transition), regional metastasis and disease recurrence with poor prognosis. Deeper analysis shows that both MEKi-resistance and SRC activation are preferentially associated with a mesenchymal CSC phenotype. This association is validated in additional independent CRC tumor and cell lines datasets. The CMS classification analysis demonstrates the strikingly-distinct associations of CMS1-4 subtypes with the MEKi-resistance and SRC activation. Importantly, MEKi + SRCi sensitivities are predicted to occur predominantly in the KRAS mutant, mesenchymal CSC-like CMS4 CRCs. Large human tumor gene expression datasets representing CRC heterogeneity can provide deep biological insights heretofore not possible with cell line models, suggesting novel repurposed drug combinations. We identified SRC as a common targetable node–-an Achilles’ heel–-in MEKi-targeted therapy-associated resistance in mesenchymal stem-like CRCs, which may help development of a biomarker-driven drug combination (MEKi + SRCi) to treat problematic subpopulations of CRC. The online version contains supplementary material available at 10.1186/s12885-022-09344-3.
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DOI：
10.1097/ppo.0b013e318238216e
发表时间：
2011-11
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Fenstermacher DA;Wenham RM;Rollison DE;Dalton WS
通讯作者：
Dalton WS
实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
影响因子：
--
作者：
Davis, Thomas B;Yang, Mingli;Pledger, W Jack
通讯作者：
Pledger, W Jack
DOI：
10.1139/o96-052
发表时间：
1996-01-01
期刊：
BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE
影响因子：
--
作者：
Bjorge, JD;OConnor, TJ;Fujita, DJ
通讯作者：
Fujita, DJ
影响因子：
4.6
作者：
Davis TB;Yang M;Schell MJ;Wang H;Ma L;Pledger WJ;Yeatman TJ
通讯作者：
Yeatman TJ