<i>KRAS/LKB1</i> and <i>KRAS/TP53</i> co-mutations create divergent immune signatures in lung adenocarcinomas

Gu, Meichen; Xu, Tongge; Chang, Pengyu

doi:10.1177/17588359211006950

Cited by 38 publications

(37 citation statements)

References 72 publications

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“…15 The underlying mechanisms are associated with deficient DNA damage caused by TP53 mutations, thus giving rise to increased genetic mutations and immunogenicity of cancer cells. 16 Meanwhile, KRAS-TP53 co-mutations increase PD-L1 expression and infiltrating immune cells than KRAS-only or TP53-only mutations, indicating a synergistic effect. 16 Similarly, we found that patients with KRAS-TP53 co-mutations had the highest ORR following immunotherapy among patients with CHOL with varied combinations of KRAS and TP53 mutation status.…”

Section: Open Accessmentioning

confidence: 98%

“…16 Meanwhile, KRAS-TP53 co-mutations increase PD-L1 expression and infiltrating immune cells than KRAS-only or TP53-only mutations, indicating a synergistic effect. 16 Similarly, we found that patients with KRAS-TP53 co-mutations had the highest ORR following immunotherapy among patients with CHOL with varied combinations of KRAS and TP53 mutation status. Moreover, patients with KRAS-only mutations had the worst prognosis and immunotherapy outcomes.…”

Section: Open Accessmentioning

confidence: 98%

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Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Chen

Wang

Liu

et al. 2021

J Immunother Cancer

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BackgroundRecently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.MethodsGenomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.ResultsKRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy.ConclusionsGenomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

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Section: Open Accessmentioning

confidence: 98%

Section: Open Accessmentioning

confidence: 98%

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Chen

Wang

Liu

et al. 2021

J Immunother Cancer

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“…KP tumors showed higher levels of somatic mutations (although the smoking burden of the included patients was similar in all three subgroups), inflammatory markers, immune checkpoint effector molecules, and longer relapse-free survival (26,27). Subsequently, Skoulidis analyzed the efficacy of antiPD-1 in advanced lines and observed higher responses in the KP versus KC subgroup (35.7% vs 7.4%), identifying STK11 as an antiPD-1 resistance mutation (28).…”

Section: Co-mutational Status Of Krasmentioning

confidence: 99%

Targeting KRAS in Non-Small Cell Lung Cancer

et al. 2022

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Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

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“…Prevalence of KRAS mutation 97.7% [9] 44.7% [9] 30.9% [9] Hottest missense mutation in KRAS G12D [9] G12D [9] G12C [9] Sensitive to glucose restriction vs. KRAS wt Yes [19] Yes [20] No [21] Common alteration with KRAS TP53 inactivation [10] TP53 and APC inactivation [22] TP53 or LKB1 inactivation [23] General milieu of KRAS-mutant tumors Immune-cold [7] Immune-cold [24] KRAS-only: immune-cold or hot [23] TP53 inactivation: immune-hot [23] LKB1 inactivation: immune-cold [23] Number General response to monotherapy using ICB drugs Poor [5] Poor [28] KRAS-only tumor: Fair [23] TP53 inactivation tumor: Excellent [23] LKB1 inactivation tumor: Poor [23] Core molecular events associated with KRAS mutation-induced immunosuppression 1. YAP-TAZ activation [12]; 2.…”

Section: Pdac Crac Luacmentioning

confidence: 99%

“…Nevertheless, KRAS mutation should not be regarded as a marker indicating immunosuppression in LUAC tumors because the immune milieu in KRAS-mutant LUAC tumors is heterogeneous. For example, the KRAS/LKB1 and KRAS/TP53 co-mutations enable LUAC patients to have dramatically different responses to ICB therapy because these two mutational patterns generally create a unique immune milieu in tumors (see details in [23]). Collectively, KRAS mutation can affect the cancer immune state in PDAC, CRAC and LUAC in different ways and contextures (Table 1).…”

Section: Value Of Kras Mutation For Predicting Cancer Immune Status In Other Adenocarcinomasmentioning

confidence: 99%

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

Gao

Chang

2021

Cancers

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Generally, patients with pancreatic ductal adenocarcinoma, especially those with wide metastatic lesions, have a poor prognosis. Recently, a breakthrough in improving their survival has been achieved by using first-line chemotherapy, such as gemcitabine plus nab-paclitaxel or oxaliplatin plus irinotecan plus 5-fluorouracil plus calcium folinate. Unfortunately, regimens with high effectiveness are still absent in second- or later-line settings. In addition, although immunotherapy using checkpoint inhibitors definitively represents a novel method for metastatic cancers, monotherapy using checkpoint inhibitors is almost completely ineffective for pancreatic ductal adenocarcinomas largely due to the suppressive immune milieu in such tumors. Critically, the genomic alteration pattern is believed to impact cancer immune environment. Surprisingly, KRAS gene mutation is found in almost all pancreatic ductal adenocarcinomas. Moreover, KRAS mutation is indispensable for pancreatic carcinogenesis. On these bases, a relationship likely exists between this oncogene and immunosuppression in this cancer. During pancreatic carcinogenesis, KRAS mutation-driven events, such as metabolic reprogramming, cell autophagy, and persistent activation of the yes-associated protein pathway, converge to cause immune evasion. However, intriguingly, KRAS mutation can dictate a different immune environment in other types of adenocarcinoma, such as colorectal adenocarcinoma and lung adenocarcinoma. Overall, the KRAS mutation can drive an immunosuppression in pancreatic ductal adenocarcinomas or in colorectal carcinomas, but this mechanism is not true in KRAS-mutant lung adenocarcinomas, especially in the presence of TP53 inactivation. As a result, the response of these adenocarcinomas to checkpoint inhibitors will vary.

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KRAS/LKB1 and KRAS/TP53 co-mutations create divergent immune signatures in lung adenocarcinomas

Cited by 38 publications

References 72 publications

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Targeting KRAS in Non-Small Cell Lung Cancer

KRAS Mutation Dictates the Cancer Immune Environment in Pancreatic Ductal Adenocarcinoma and Other Adenocarcinomas

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