Targeting <i>KRAS</i>: Crossroads of Signaling and Immune Inhibition

Kato, Shumei; Fujiwara, Yu; Hong, David S.

doi:10.36401/jipo-22-5

Cited by 10 publications

(10 citation statements)

References 90 publications

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“…This study highlighted the potential for combining immunotherapy with KRAS inhibitors in KRAS -mutated BTCs. The results showed that GBC had a relative higher mean and median TMB and proportion of PD-L1 high expression, which are favorable factors for ICI therapy response in KRAS -mutated GBC . In a 2023 study by Jeong et al, patients with KRAS allelic variants and PD-L1 positivity had a longer progression-free survival than patients with KRAS allelic variants and PD-L1 negativity.…”

Section: Discussionmentioning

confidence: 97%

“…The results showed that GBC had a relative higher mean and median TMB and proportion of PD-L1 high expression, which are favorable factors for ICI therapy response in KRAS -mutated GBC. 42 In a 2023 study by Jeong et al, 43 patients with KRAS allelic variants and PD-L1 positivity had a longer progression-free survival than patients with KRAS allelic variants and PD-L1 negativity. Preclinically, KRAS inhibitors have been associated with promotion of a proinflammatory tumor microenvironment, increased major histocompatibility complex class I protein expression, and synergies with immunotherapy to enhance antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

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KRAS Allelic Variants in Biliary Tract Cancers

Moffat,

Hu,

Meric-Bernstam

et al. 2024

JAMA Netw Open

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ImportanceBiliary tract cancers (BTCs) contain several actionable molecular alterations, including FGFR2, IDH1, ERBB2 (formerly HER2), and KRAS. KRAS allelic variants are found in 20% to 30% of BTCs, and multiple KRAS inhibitors are currently under clinical investigation.ObjectivesTo describe the genomic landscape, co–sequence variations, immunophenotype, genomic ancestry, and survival outcomes of KRAS-mutated BTCs and to calculate the median overall survival (mOS) for the most common allelic variants.Design, Setting, and ParticipantsThis retrospective, multicenter, pooled cohort study obtained clinical and next-generation sequencing data from multiple databases between January 1, 2017, and December 31, 2022. These databases included Princess Margaret Cancer Centre, MD Anderson Cancer Center, Foundation Medicine, American Association for Cancer Research Project GENIE, and cBioPortal for Cancer Genomics. The cohort comprised patients with BTCs who underwent genomic testing.Main Outcome and MeasureThe main outcome was mOS, defined as date of diagnosis to date of death, which was measured in months.ResultsA total of 7457 patients (n = 3773 males [50.6%]; mean [SD] age, 63 [5] years) with BTCs and genomic testing were included. Of these patients, 5813 had clinical outcome data available, in whom 1000 KRAS-mutated BTCs were identified. KRAS allelic variants were highly prevalent in perihilar cholangiocarcinoma (28.6%) and extrahepatic cholangiocarcinoma (36.1%). Thirty-six KRAS allelic variants were identified, and the prevalence rates in descending order were G12D (41%), G12V (23%), and Q61H (8%). The variant G12D had the highest mOS of 25.1 (95% CI, 22.0-33.0) months compared with 22.8 (95% CI, 19.6-31.4) months for Q61H and 17.8 (95% CI, 16.3-23.1) months for G12V variants. The majority of KRAS-mutated BTCs (98.9%) were not microsatellite instability–high and had low tumor mutational burden (ranging from a median [IQR] of 1.2 (1.2-2.5) to a mean [SD] of 3.3 [1.3]). Immune profiling through RNA sequencing of KRAS and NRAS–mutated samples showed a pattern toward a more immune-inflamed microenvironment with higher M1 macrophage activation (0.16 vs 0.12; P = .047) and interferon-γ expression compared with wild-type tumors. The G12D variant remained the most common KRAS allelic variant in all patient ancestries. Patients with admixed American ancestry had the highest proportion of G12D variant (45.0%).Conclusions and RelevanceThis cohort study found that KRAS allelic variants were relatively common and may be potentially actionable genomic alterations in patients with BTCs, especially perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma. The findings add to the growing data on genomic and immune landscapes of KRAS allelic variants in BTCs and are potentially of value to the planning of specific therapies for this heterogeneous patient group.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

KRAS Allelic Variants in Biliary Tract Cancers

Moffat,

Hu,

Meric-Bernstam

et al. 2024

JAMA Netw Open

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“…Responses to ICIs that block PD-1/PD-L1 may be highly dependent on concurrent mutations 178 . According to several studies, although ICIs can effectively treat patients with gastrointestinal cancers or NSCLC harboring a KRAS mutation, primary or acquired resistance to ICIs may occur 179 . Targeted next-generation sequencing of lung adenocarcinoma revealed that KRAS mutation with TP53 and MET mutations is strongly linked to increased PD-L1 expression 180 .…”

Section: Treatments Targeting Kras and The Tmementioning

confidence: 99%

Impact of KRAS mutation on the tumor microenvironment in colorectal cancer

Zhou,

Kuang,

Wang

et al. 2024

Int. J. Biol. Sci.

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Kirsten rat sarcoma viral oncogene homolog (KRAS) is an oncogene implicated in the pathophysiology of many cancers. Increasing evidence shows that KRAS mutation is correlated with poor prognosis in numerous cancers, including colorectal cancer (CRC), breast cancer, and melanoma. KRAS also participates in regulating the CRC microenvironment. However, the direct and indirect therapeutic targets of KRAS in CRC have not been identified; thus, elucidating the mechanisms and interactions between KRAS and the tumor microenvironment (TME) in-depth is paramount. Herein, we present some of the major roles KRAS plays in shaping the heterogeneity of the TME and propose a potential strategy for targeting the downstream components of the KRAS signaling pathway and the TME in CRC.

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“…This group of genes is involved in the control of cell growth, survival, differentiation and potentially shaping the local tumour-immune microenvironment [9,10], and is frequently associated with genomic alterations in human cancers. KRAS is the most commonly mu-tated RAS isoform, making up approximately 85% of oncogenic RAS mutations in all cancer types [11]. KRAS mutations are seen in 61-86% of pancreatic ductal adenocarcinomas, 33-52% of colorectal adenocarcinomas, and 17-32% of lung adenocarcinomas.…”

Section: Kras Mutations: Biology and Signaling Pathwaysmentioning

confidence: 99%

Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC

et al. 2023

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Activating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS), in particular, a point mutation leading to a glycine-to-cysteine substitution at codon 12 (G12C), are among the most frequent genomic alterations in non-small cell lung cancer (NSCLC). Several agents targeting KRAS G12C have recently entered clinical development. Sotorasib, a first-in-class specific small molecule that irreversibly inhibits KRAS G12C, has since obtained Health Canada approval. The emergence of novel KRAS-targeted therapies warrants the development of evidence-based consensus recommendations to help clinicians better understand and contextualize the available data. A Canadian expert panel was convened to define the key clinical questions, review recent evidence, and discuss and agree on recommendations for the treatment of advanced KRAS G12C-mutated NSCLC. The panel agreed that testing for KRAS G12C should be performed as part of a comprehensive panel that includes current standard-of-care biomarkers. Sotorasib, the only approved KRAS G12C inhibitor in Canada, is recommended for patients with advanced KRAS G12C-mutated NSCLC who progressed on guideline-recommended first-line standard of care for advanced NSCLC without driver alterations (immune-checkpoint inhibitor(s) [ICIs] +/− chemotherapy). Sotorasib could also be offered as second-line therapy to patients who progressed on ICI monotherapy that are not candidates for a platinum doublet and those that received first-line chemotherapy with a contraindication to ICIs. Preliminary data indicate the activity of KRAS G12C inhibitors in brain metastases; however, the evidence is insufficient to make specific recommendations. Regular liver function monitoring is recommended when patients are prescribed KRAS G12C inhibitors due to risk of hepatotoxicity.

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Targeting KRAS: Crossroads of Signaling and Immune Inhibition

Cited by 10 publications

References 90 publications

KRAS Allelic Variants in Biliary Tract Cancers

KRAS Allelic Variants in Biliary Tract Cancers

Impact of KRAS mutation on the tumor microenvironment in colorectal cancer

Canadian Consensus Recommendations on the Management of KRAS G12C-Mutated NSCLC

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