01
This study was designed to conduct a comprehensive exploration of biallelic inactivation in tumor suppressor genes (TSGs) within a vast cohort of cancer patients. The researchers utilized the MSK - IMPACT targeted clinical sequencing assay to scrutinize the tumor profiles of 48,179 patients with 67 major cancer subtypes. They began by characterizing the somatic biallelic inactivation in TSGs and noted that while a significant proportion of oncogenic somatic alterations in TSGs were linked to biallelic inactivation, the rate and mechanism of this inactivation varied considerably across different genes and tumor lineages. Through quantitative analysis, they established the selective pressure for biallelic inactivation and categorized TSGs into four classes based on their propensity to lose or retain the wild - type allele. During this investigation, they uncovered rare driver TSG events, such as the case of APC in prostate and lung adenocarcinomas. Additionally, they found that Wnt pathway mutations in these cancers emerged late and possessed biologically important characteristics. They also made the discovery that the selection for MutLOH could reclassify functional variants of uncertain significance (VUSs). Notably, KEAP1 VUSs in LUAD demonstrated evidence of functionality and patient outcomes similar to oncogenic alleles. Moreover, they showed that KEAP1 mutant zygosity functioned as a prognostic biomarker for standard therapies in LUAD. Patients with biallelic alterations in KEAP1 had inferior overall survival and a poorer response to immunotherapy in contrast to those with monoallelic alterations or wild - type KEAP1.
In summary, this study provided fresh perspectives on the role of TSGs in cancer and emphasized the potential of using zygosity as a biomarker for predicting therapeutic responses, which holds great promise for future cancer research and clinical practice, potentially leading to more personalized treatment approaches and enhanced patient outcomes. It also underlined the necessity of further probing into the intricate genetic alterations in cancer and their correlations with treatment efficacy and prognosis.
DOI: 10.1016/j.cell.2024.11.010
02
This study delves into the significance of KEAP1 in non-small cell lung cancer (NSCLC). The researchers initially explored the gene mutations in LUAD and LUSC using the TCGA database and discovered a high mutation rate of KEAP1 in both. Subsequent experiments with lung cancer cell lines, including knockdown and overexpression of KEAP1, firmly established that KEAP1 functions as a tumor suppressor. It inhibits cell growth and colony formation, and this inhibitory effect is mediated, at least in part, by its negative regulation of the PI3K-AKT signaling pathway.
A crucial finding of this study is the direct interaction between KEAP1 and PD-L1. Through a series of techniques such as mass spectrometry, immunoprecipitation assays, and GST pull - down assays, the interaction was clearly demonstrated. Moreover, KEAP1 was shown to promote the ubiquitination and degradation of PD-L1 via the 26S proteasome pathway, independent of NRF2. This degradation of PD-L1 has a profound impact on the tumor microenvironment. It leads to an increase in the number of CD8 T cells and the activation of these cells, thereby enhancing the anti - tumor immune response.In vivo experiments provided further evidence of the role of KEAP1 in tumor growth and survival. Overexpression of KEAP1 in mouse models inhibited tumor growth and prolonged survival. Additionally, the combination of KEAP1 overexpression and anti-PD-L1 treatment had a synergistic effect, further suppressing tumor progression.Clinical analysis of tissue microarrays and patient samples added a translational aspect to the study. A negative correlation between KEAP1 and PD-L1 expression was observed, and patients with high KEAP1 and low PD-L1 levels had a better prognosis. This finding suggests that KEAP1 could potentially serve as a biomarker for predicting patient outcomes and as a target for improving anti-PD-L1 immunotherapy in NSCLC. Overall, this study uncovers a novel mechanism by which KEAP1 regulates PD-L1 and impacts anti-tumor immunity, opening new avenues for the development of more effective treatments for NSCLC.
DOI: 10.1038/s41419-024-06563-3
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Editor & Reviewer: Yanwen Zhu
