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Beyond the Genomic Mutation: Rethinking the Molecular Biomarkers of K-RAS Dependency in Pancreatic Cancers.

ABSTRACT: Oncogenic v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) plays a key role in the development and maintenance of pancreatic ductal adenocarcinoma (PDAC). The targeting of K-RAS would be beneficial to treat tumors whose growth depends on active K-RAS. The analysis of K-RAS genomic mutations is a clinical routine; however, an emerging question is whether the mutational status is able to identify tumors effectively dependent on K-RAS for tailoring targeted therapies. With the emergence of novel K-RAS inhibitors in clinical settings, this question is relevant. Several studies support the notion that the K-RAS mutation is not a sufficient biomarker deciphering the effective dependency of the tumor. Transcriptomic and metabolomic profiles of tumors, while revealing K-RAS signaling complexity and K-RAS-driven molecular pathways crucial for PDAC growth, are opening the opportunity to specifically identify K-RAS-dependent- or K-RAS-independent tumor subtypes by using novel molecular biomarkers. This would help tumor selection aimed at tailoring therapies against K-RAS. In this review, we will present studies about how the K-RAS mutation can also be interpreted in a state of K-RAS dependency, for which it is possible to identify specific K-RAS-driven molecular biomarkers in certain PDAC subtypes, beyond the genomic K-RAS mutational status.

SUBMITTER: Mottini C

PROVIDER: S-EPMC7404119 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Beyond the Genomic Mutation: Rethinking the Molecular Biomarkers of K-RAS Dependency in Pancreatic Cancers.

Mottini Carla C Cardone Luca L

International journal of molecular sciences 20200716 14

Oncogenic v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) plays a key role in the development and maintenance of pancreatic ductal adenocarcinoma (PDAC). The targeting of K-RAS would be beneficial to treat tumors whose growth depends on active K-RAS. The analysis of <i>K-RAS</i> genomic mutations is a clinical routine; however, an emerging question is whether the mutational status is able to identify tumors effectively dependent on K-RAS for tailoring targeted therapies. With the em ...[more]

PMID: 32708716

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Project description:ImportanceUnderstanding RAS dependency and mechanisms of RAS activation in non-V600 BRAF variant cancers has important clinical implications. This is the first study to date to systematically assess RAS dependency of BRAF alterations with real-world cancer genomic databases.ObjectiveTo evaluate RAS dependency of individual BRAF alterations through alteration coexistence analysis using cancer genomic databases.Design and settingA cross-sectional data analysis of 119 538 nonredundant cancer samples using cancer genomics databases including GENIE (Genomics Evidence Neoplasia Information Exchange) and databases in cBioPortal including TCGA (The Cancer Genome Atlas) (accessed March 24, 2020), in addition to 2745 cancer samples from Mayo Clinic Genomics Laboratory (January 1, 2015, to July 1, 2020). Frequencies and odds ratios of coexisting alterations of RAS (KRAS, NRAS and HRAS) and RAS regulatory genes (NF1, PTPN11 and CBL) were calculated for individual BRAF alterations, and compared according to the current BRAF alteration classification; cancer type specificity of coexisting alterations of RAS or RAS regulatory genes was also evaluated.Main outcomes and measuresPrimary outcome measurement is enrichment of RAS (KRAS, NRAS and HRAS) alterations in BRAF variant cancers. Secondary outcome measurement is enrichment of RAS regulatory gene (NF1, PTPN11, and CBL) in BRAF variant cancers.ResultsA total of 2745 cancer samples from 2708 patients (female/male ratio: 1.0) tested by Mayo Clinic Genomics Laboratory and 119 538 patients (female/male ratio: 1.1) from GENIE and cBioPortal database were included in the study. In 119 538 nonredundant cancer samples, class 1 BRAF alterations and BRAF fusions were found to be mutually exclusive to alterations of RAS or RAS regulatory genes (odds ratio range 0.03-0.13 and 0.03-0.73 respectively), confirming their RAS independency. Both class 2 and class 3 BRAF alterations show variable and overlapping levels of enriched RAS alterations (odds ratio range: 0.03-5.9 and 0.63-2.52 respectively), suggesting heterogeneity in RAS dependency and a need to revisit BRAF alteration classification. For RAS-dependent BRAF alterations, the coexisting alterations also involve RAS regulatory genes by enrichment analysis (for example, S467L shows an odds ratio of 8.26 for NF1, 9.87 for PTPN11, and 15.23 for CBL) and occur in a variety of cancer types with some coalterations showing cancer type specificity (for example, HRAS variations account for 46.7% of all coexisting RAS alterations in BRAF variant bladder cancers, but 0% in non-small cell lung cancers). Variant-level assessment shows that BRAF alterations involving the same codon may differ in RAS dependency. In addition, RAS dependency of previously unclassified BRAF alterations could be assessed.Conclusions and relevanceCurrent BRAF alteration classification based on in vitro assays does not accurately predict RAS dependency in vivo for non-V600 BRAF alterations. RAS-dependent BRAF variant cancers with different mechanisms of RAS activation suggest the need for different treatment strategies.

Project description:Pancreatic cancer is an increasing cause of cancer related death worldwide. KRAS is the dominant oncogene in this cancer type and molecular rationale would indicate, that inhibitors of the downstream target MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular biomarkers that can help to define subgroups where MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical pancreatic cancer samples to identify the molecular subtypes of pancreatic cancer these cell lines represent. Luminescent cell viability assay was used to determine the sensitivity of cell lines to kinase inhibitors. Western blot was used to analyze the pathway activity of the examined cell lines. According to our cell viability and pathway activity data on these model cell lines only cells harboring the rare G12C KRAS mutation and low EGFR expression are sensitive to single MEK inhibitor (trametinib) treatment. The common G12D KRAS mutation leads to elevated baseline Akt activity, thus treatment with single MEK inhibitors fails. However, combination of MEK and Akt inhibitors are synergistic in this case. In case of wild-type KRAS and high EGFR expression MEK inhibitor induced Akt phosphorylation leads to trametinib resistance which necessitates for MEK and EGFR or Akt inhibitor combination treatment. In all we provide strong preclinical rational and possible molecular mechanism to revisit MEK inhibitor therapy in pancreatic cancer in both monotherapy and combination, based on molecular profile analysis of pancreatic cancer samples and cell lines. According to our most remarkable finding, a small subgroup of patients with G12C KRAS mutation may still benefit from MEK inhibitor monotherapy.

Dataset Information

Beyond the Genomic Mutation: Rethinking the Molecular Biomarkers of K-RAS Dependency in Pancreatic Cancers.

Publications

Beyond the Genomic Mutation: Rethinking the Molecular Biomarkers of K-RAS Dependency in Pancreatic Cancers.

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