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

Cancer Discovery, Journal Year: 2018, Volume and Issue: 8(7), P. 822 - 835

Published: May 17, 2018

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 efficacy PD-1 inhibitors these subgroups. Objective response rates to blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) (P < 0.001) Stand Up To Cancer (SU2C) cohort (174 patients) with LUAC patients treated nivolumab CheckMate-057 phase III trial (0% vs. 57.1% 18.2%; P = 0.047). In SU2C cohort, exhibited shorter progression-free overall 0.0015) survival compared KRASMUT;STK11/LKB1WT Among 924 LUACs, alterations were only marker associated PD-L1 negativity TMBIntermediate/High The impact on clinical outcomes PD-1/PD-L1 extended PD-L1–positive non–small cell cancer. Kras-mutant murine models, Stk11/Lkb1 loss promoted inhibitor resistance, suggesting a causal role. Our results identify as major primary resistance Significance: This work identifies prevalent genomic axis adenocarcinoma. Genomic profiling may enhance predictive utility expression tumor mutation burden facilitate establishment personalized combination immunotherapy approaches for genomically defined subsets. Discov; 8(7); 822–35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794. article highlighted Issue feature, 781

Language: Английский

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Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy

Science, Journal Year: 2017, Volume and Issue: 355(6322)

Published: Jan. 19, 2017

Chromosomal chaos and tumor immunity Cancer immunotherapy produces durable clinical responses in only a subset of patients. Identification characteristics that correlate with could lead to predictive biomarkers shed light on causal mechanisms. Davoli et al. found human tumors extensive aneuploidy—i.e., display highly abnormal number chromosomes chromosomal segments—express fewer markers the immune cells responsible for destruction. In retrospective analysis trial data, they melanoma patients aneuploid were less likely benefit from checkpoint blockade therapy than whose had more normal karyotype. Thus, aneuploidy appears enhance ability evade system. Science , this issue p. 10.1126/science.aaf8399

Language: Английский

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Mechanisms of resistance to immune checkpoint inhibitors

British Journal of Cancer, Journal Year: 2018, Volume and Issue: 118(1), P. 9 - 16

Published: Jan. 1, 2018

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clinical activity in several types of cancer are rapidly transforming practice medical oncology. Whereas cytotoxic chemotherapy small molecule ('targeted therapies') largely act on cells directly, immune reinvigorate anti-tumour responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops patients treated with conventional therapies targeted therapies, durable suggestive long-lasting immunologic memory commonly seen large subsets ICI. However, initial response appears to be a binary event, most non-responders single-agent ICI therapy progressing at rate consistent natural history disease. In addition, late relapses now emerging longer follow-up trial populations, suggesting emergence acquired resistance. As robust biomarkers predict and/or remain elusive, mechanisms underlying innate (primary) (secondary) inferred from pre-clinical studies correlative data. Improved understanding molecular (and resistance) may not only identify novel predictive prognostic biomarkers, but also ultimately guide optimal combination/sequencing clinic. Here we review data identifying inhibition.

Language: Английский

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STING: infection, inflammation and cancer

Nature reviews. Immunology, Journal Year: 2015, Volume and Issue: 15(12), P. 760 - 770

Published: Nov. 25, 2015

Language: Английский

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Type I interferons in anticancer immunity

Nature reviews. Immunology, Journal Year: 2015, Volume and Issue: 15(7), P. 405 - 414

Published: June 1, 2015

Language: Английский

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