Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
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DOI：
10.1158/2159-8290.cd-14-1236
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发表时间：
2015-08
期刊：
影响因子：
28.2
通讯作者：
Heymach JV
中科院分区：
文献类型：
--
作者：
Skoulidis F;Byers LA;Diao L;Papadimitrakopoulou VA;Tong P;Izzo J;Behrens C;Kadara H;Parra ER;Canales JR;Zhang J;Giri U;Gudikote J;Cortez MA;Yang C;Fan Y;Peyton M;Girard L;Coombes KR;Toniatti C;Heffernan TP;Choi M;Frampton GM;Miller V;Weinstein JN;Herbst RS;Wong KK;Zhang J;Sharma P;Mills GB;Hong WK;Minna JD;Allison JP;Futreal A;Wang J;Wistuba II;Heymach JV
驱动KRAS突变型肺腺癌（LUAC）异质性的分子基础尚不清楚。我们对早期和化学难治性LUAC的基因组、转录组和蛋白质组数据进行了综合分析，并确定了KRAS突变LUAC的三个稳健子集，分别由STK 11/LKB 1（KL亚群）、TP 53（KP）和CDKN 2A/B失活中共同发生的遗传事件以及NKX 2 -1（TTF 1）转录因子（KC）的低表达所主导。我们进一步揭示了亚组之间的生物学和治疗相关差异。KC肿瘤经常表现出粘液组织学和抑制mTORC 1信号。KL肿瘤具有高KEAP 1突变失活率，并表达较低水平的免疫标志物，包括PD-L1。KP肿瘤表现出更高水平的体细胞突变、炎症标志物、免疫检查点效应分子和改善的无复发生存期。还观察到药物敏感性模式的差异;值得注意的是，KL细胞对HSP 90抑制剂治疗的脆弱性增加。这项工作提供的证据表明，共同发生的基因组改变确定亚组的KRAS突变LUAC具有不同的生物学和治疗的弱点。
The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma (LUAC) are poorly characterized. We performed an integrative analysis of genomic, transcriptomic and proteomic data from early-stage and chemo-refractory LUAC and identified three robust subsets of KRAS-mutant LUAC dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL subgroup), TP53 (KP) and CDKN2A/B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further reveal biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of KEAP1 mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant LUAC with distinct biology and therapeutic vulnerabilities.