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STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma.


ABSTRACT: KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations 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 Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III 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 (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, 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 non-small cell lung cancer. 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.Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7); 822-35. ©2018 AACR.See related commentary by Etxeberria et al., p. 794This article is highlighted in the In This Issue feature, p. 781.

SUBMITTER: Skoulidis F 

PROVIDER: S-EPMC6030433 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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<i>STK11/LKB1</i> Mutations and PD-1 Inhibitor Resistance in <i>KRAS</i>-Mutant Lung Adenocarcinoma.

Skoulidis Ferdinandos F   Goldberg Michael E ME   Greenawalt Danielle M DM   Hellmann Matthew D MD   Awad Mark M MM   Gainor Justin F JF   Schrock Alexa B AB   Hartmaier Ryan J RJ   Trabucco Sally E SE   Gay Laurie L   Ali Siraj M SM   Elvin Julia A JA   Singal Gaurav G   Ross Jeffrey S JS   Fabrizio David D   Szabo Peter M PM   Chang Han H   Sasson Ariella A   Srinivasan Sujaya S   Kirov Stefan S   Szustakowski Joseph J   Vitazka Patrik P   Edwards Robin R   Bufill Jose A JA   Sharma Neelesh N   Ou Sai-Hong I SI   Peled Nir N   Spigel David R DR   Rizvi Hira H   Aguilar Elizabeth Jimenez EJ   Carter Brett W BW   Erasmus Jeremy J   Halpenny Darragh F DF   Plodkowski Andrew J AJ   Long Niamh M NM   Nishino Mizuki M   Denning Warren L WL   Galan-Cobo Ana A   Hamdi Haifa H   Hirz Taghreed T   Tong Pan P   Wang Jing J   Rodriguez-Canales Jaime J   Villalobos Pamela A PA   Parra Edwin R ER   Kalhor Neda N   Sholl Lynette M LM   Sauter Jennifer L JL   Jungbluth Achim A AA   Mino-Kenudson Mari M   Azimi Roxana R   Elamin Yasir Y YY   Zhang Jianjun J   Leonardi Giulia C GC   Jiang Fei F   Wong Kwok-Kin KK   Lee J Jack JJ   Papadimitrakopoulou Vassiliki A VA   Wistuba Ignacio I II   Miller Vincent A VA   Frampton Garrett M GM   Wolchok Jedd D JD   Shaw Alice T AT   Jänne Pasi A PA   Stephens Philip J PJ   Rudin Charles M CM   Geese William J WJ   Albacker Lee A LA   Heymach John V JV  

Cancer discovery 20180517 7


<i>KRAS</i> is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that <i>STK11/LKB1</i> (KL) or <i>TP53</i> (KP) comutations define distinct subgroups of <i>KRAS</i>-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 (<i>P</i> < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with <i>KRAS</i>-m  ...[more]

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