KRASG12C/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (≥50%) lung adenocarcinoma

Frost, Nikolaj; Kollmeier, Jens; Vollbrecht, Claudia; Grah, Christian; Matthes, Burkhard; Pultermann, Dennis; Laffert, Maximilian von; Lüders, H; Olivé, Elisa Llurba; Raspe, Matthias; Mairinger, Thomas; Ochsenreither, Sebastian; Blum, Torsten; Hummel, Michael; Suttorp, Norbert; Witzenrath, Martin; Grohé, Christian

doi:10.21037/tlcr-20-958

Cited by 40 publications

(29 citation statements)

References 47 publications

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“…mutational burden and immune checkpoint inhibitor sensitivity among non-G12C KRAS-mutant subtypes. Early data suggest that the presence of KRAS alleles other than G12C mutations (75), especially in conjunction with a TP53 comutation, may represent a negative predictive biomarkers for anti-PD-1/PD-L1 immune checkpoint inhibitors in patients with NSCLC (76). We expect the coming years in the field of KRAS-mutant NSCLC to be very insightful in particular because of the translation of learnings from the KRAS G12C inhibitor field on combinations and comutations to non-G12C KRAS-mutated cancers.…”

Section: Reviewmentioning

confidence: 99%

Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

et al. 2022

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KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRAS G12C inhibitors are currently changing the treatment paradigm for patients with KRAS G12C -mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRAS G12D -, KRAS G12V -, KRAS G13D -, KRAS G12R -, and KRAS G12A -mutant or KRAS wild-typeamplified cancers, as well as cancers with acquired resistance to KRAS G12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility.Significance: Mutant-selective KRAS G12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRASdriven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

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Section: Reviewmentioning

confidence: 99%

Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

et al. 2022

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“…Finally, results from real-world data published by Frost et al from a multicenter, retrospective study evaluated the efficacy of first-line pembrolizumab in 119 patients with KRAS mutant LuAD with high PD-L1 expression (≥50%). Co-mutations in TP53 were also evaluated, and patients with KRAS G12C/TP53 had significantly higher ORR (100% vs 27.3%; p = 0.003) and longer mPFS (33.3 vs 2.8 months; HR, 0.18; 95% CI: 0.06-0.53; p = 0.002) than tumors with KRAS nonG12C/TP53 mutations (41), suggesting that KRAS G12C present better outcomes to immune-based therapies. Furthermore, Noordhof et al reported another retrospective study that evaluated the outcomes of first-line pembrolizumab in 595 patients with metastatic LuAD and high PD-L1 expression.…”

Section: The Efficacy Of Current Immunotherapies In Lung Cancers With...mentioning

confidence: 99%

Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

Cucurull¹,

Notario²,

Sanchez-Cespedes³

et al. 2022

Front. Oncol.

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Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was considered “undruggable” for decades, specific KRAS G12C covalent inhibitors have recently emerged, although their promising results are limited to a subset of patients. Several other drugs targeting KRAS activation and downstream signaling pathways are currently under investigation in early-phase clinical trials. In addition, KRAS mutations can co-exist with other mutations in significant genes in cancer (e.g., STK11 and KEAP1) which induces tumor heterogeneity and promotes different responses to therapies. This review describes the molecular characterization of KRAS mutant lung cancers from a biologic perspective to its clinical implications. We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.

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“…In this study, the BTG2 was correlated to TP53 and ROS1 mutations, but not EGFR , indicating that BTG2 might be involved in the effect of TP53 - or ROS1 ‐mutations on immune activity, and closely associated with immunity. 44 , 77 , 78 , 84 , 85 …”

Section: Discussionmentioning

confidence: 99%

BTG2 Serves as a Potential Prognostic Marker and Correlates with Immune Infiltration in Lung Adenocarcinoma

Zhang¹,

Chen²,

Fan³

et al. 2022

IJGM

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Background B-cell translocation gene 2 ( BTG2 ) has been revealed to be involved in the occurrence and development of multiple cancers. However, the role of BTG2 in lung adenocarcinoma (LUAD) is still ambiguous. Thus, this study aims to investigate the prognostic value of BTG2 and its correlation with immune infiltration in LUAD. Methods The expression of BTG2 in LUAD was analyzed using the TIMER and UALCAN databases. The correlations between BTG2 expression and clinicopathological factors were investigated using the UALCAN databases. The Kaplan–Meier plotter, GEPIA, and TCGA databases were employed to assess the prognostic value of BTG2 . The STRING database and Cytoscape software were used to construct an interaction network and mine co-expression genes. The TISIDB database was examined for a correlation between BTG2 and driver genes in LUAD. Enrichment analysis of co-expressed genes and BTG2 was performed using the LinkedOmics database. Finally, the correlations between BTG2 and immune infiltrates were investigated using the TIMER, GEO, and TISIDB database. Results BTG2 was significantly downregulated in LUAD. The decreased expression of BTG2 in LUAD was significantly correlated with higher cancer stages and shorter duration of overall survival. The expressions of BTG2 -related co-expression genes were associated with the prognosis in LUAD. The expression of BTG2 was closely associated with the mutations of TP53 and ROS1 . Enrichment analysis revealed that BTG2 was significantly correlated with immune‐associated signaling pathways and function. In addition, the expression of BTG2 was found to be closely related to immune infiltration, multiple gene markers of immune cells, chemokines, and chemokine receptors. Conclusion Our findings have effectively demonstrated that BTG2 expression was downregulated in LUAD, indicating poor prognosis. Closely relating to immune cell infiltration, BTG2 may be a promising immune-related biomarker and molecular target for patients with LUAD.

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KRASG12C/TP53 co-mutations identify long-term responders to first line palliative treatment with pembrolizumab monotherapy in PD-L1 high (≥50%) lung adenocarcinoma

Cited by 40 publications

References 47 publications

Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants

Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

BTG2 Serves as a Potential Prognostic Marker and Correlates with Immune Infiltration in Lung Adenocarcinoma

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