STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma.
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma.
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DOI：
10.1158/2159-8290.cd-18-0099
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发表时间：
2018-07
期刊：
影响因子：
28.2
通讯作者：
Heymach JV
中科院分区：
文献类型：
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作者：
Skoulidis F;Goldberg ME;Greenawalt DM;Hellmann MD;Awad MM;Gainor JF;Schrock AB;Hartmaier RJ;Trabucco SE;Gay L;Ali SM;Elvin JA;Singal G;Ross JS;Fabrizio D;Szabo PM;Chang H;Sasson A;Srinivasan S;Kirov S;Szustakowski J;Vitazka P;Edwards R;Bufill JA;Sharma N;Ou SI;Peled N;Spigel DR;Rizvi H;Aguilar EJ;Carter BW;Erasmus J;Halpenny DF;Plodkowski AJ;Long NM;Nishino M;Denning WL;Galan-Cobo A;Hamdi H;Hirz T;Tong P;Wang J;Rodriguez-Canales J;Villalobos PA;Parra ER;Kalhor N;Sholl LM;Sauter JL;Jungbluth AA;Mino-Kenudson M;Azimi R;Elamin YY;Zhang J;Leonardi GC;Jiang F;Wong KK;Lee JJ;Papadimitrakopoulou VA;Wistuba II;Miller VA;Frampton GM;Wolchok JD;Shaw AT;Jänne PA;Stephens PJ;Rudin CM;Geese WJ;Albacker LA;Heymach JV
KRAS是肺腺癌（LUAC）中最常见的致癌驱动因子。我们之前报道过STK11/LKB1 （KL）或TP53 （KP）共突变定义了kras突变体LUAC的不同亚群。在这里，我们检查PD-1抑制剂在这些亚组中的疗效。在SU2C队列（174例患者）中，kras突变LUAC患者的KL亚组（7.4%）、KP亚组（35.7%）和K-only亚组（28.6%）对PD-1阻断的客观反应率差异显著（P<0.001），在CheckMate-057 3期试验中接受nivolumab治疗的患者中（0% vs 57.1% vs 18.2%， P=0.047）。在SU2C队列中，与KRASMUT相比，KL LUAC表现出更短的无进展（P<0.001）和总生存期（P=0.0015）；STK11 / LKB1WT LUAC。在924例LUAC中，STK11/LKB1改变是唯一与tmb中/高LUAC中PD-L1阴性显著相关的标志物。STK11/LKB1改变对PD-1/PD-L1抑制剂临床结果的影响扩展到PD-L1阳性NSCLC。在kras突变小鼠LUAC模型中，Stk11/Lkb1缺失促进了PD-1/PD-L1抑制剂的耐药，这表明两者之间存在因果关系。我们的研究结果表明，STK11/LKB1的改变是kras突变型LUAC对PD-1阻断的原发性耐药的主要驱动因素。
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) co-mutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P<0.001) in the SU2C cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase 3 trial (0% vs 57.1% vs 18.2%, P=0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P<0.001) and overall survival (P=0.0015) compared to KRASMUT;STK11/LKB1WT LUAC. Among 924 LUAC, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive NSCLC. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC.