STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma Journal Article
| Authors: | Skoulidis, F.; Goldberg, M. E.; Greenawalt, D. M.; Hellmann, M. D.; Awad, M. M.; Gainor, J. F.; Schrock, A. B.; Hartmaier, R. J.; Trabucco, S. E.; Gay, L.; Ali, S. M.; Elvin, J. A.; Singal, G.; Ross, J. S.; Fabrizio, D.; Szabo, P. M.; Chang, H.; Sasson, A.; Srinivasan, S.; Kirov, S.; Szustakowski, J.; Vitazka, P.; Edwards, R.; Bufill, J. A.; Sharma, N.; Ou, S. H. I.; Peled, N.; Spigel, D. R.; Rizvi, H.; Aguilar, E. J.; Carter, B. W.; Erasmus, J.; Halpenny, D. F.; Plodkowski, A. J.; Long, N. M.; Nishino, M.; Denning, W. L.; Galan-Cobo, A.; Hamdi, H.; Hirz, T.; Tong, P.; Wang, J.; Rodriguez-Canales, J.; Villalobos, P. A.; Parra, E. R.; Kalhor, N.; Sholl, L. M.; Sauter, J. L.; Jungbluth, A. A.; Mino-Kenudson, M.; Azimi, R.; Elamin, Y. Y.; Zhang, J.; Leonardi, G. C.; Jiang, F.; Wong, K. K.; Lee, J. J.; Papadimitrakopoulou, V. A.; Wistuba, I. I.; Miller, V. A.; Frampton, G. M.; Wolchok, J. D.; Shaw, A. T.; Jänne, P. A.; Stephens, P. J.; Rudin, C. M.; Geese, W. J.; Albacker, L. A.; Heymach, J. V. |
| Article Title: | 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 dis tinct 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. © 2018 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 8 |
| Issue: | 7 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2018-07-01 |
| Start Page: | 822 |
| End Page: | 835 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-18-0099 |
| PROVIDER: | scopus |
| PMCID: | PMC6030433 |
| PUBMED: | 29773717 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 August 2018 -- Source: Scopus |
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