Impact of RAS mutation subtype on clinical outcome—a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer

Wiesweg, Marcel; Kasper, Stefan; Worm, Karl; Herold, Thomas; Reis, Henning; Sara, Linda; Metzenmacher, Martin; Abendroth, Annalena; Darwiche, Kaid; Aigner, Clemens; Wedemeyer, Heiner; Helfritz, Fabian; Stuschke, Martin; Schumacher, Brigitte; Markus, Peter M.; Paul, Andreas; Rahmann, Sven; Schmid, Kurt Werner; Schüler, Martin

doi:10.1038/s41388-018-0634-0

Cited by 42 publications

(48 citation statements)

References 65 publications

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“…The other important issue is the clinical relevance of specific KRAS mutations and the presence of these mutations in combination with others. Variations in KRAS mutation subtypes have been associated with distinct biological behaviors that can lead to different clinical outcomes [16,17]. For example, tumors with KRAS G12C mutations exhibited higher ERK1/2 phosphorylation than those with KRAS G12D [3,18].…”

Section: Clinical Relevance Of Kras Mutations In Nsclcmentioning

confidence: 99%

Current therapy of KRAS-mutant lung cancer

Ghimessy

Radeczky

László

et al. 2020

Cancer Metastasis Rev

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KRAS mutations are the most frequent gain-of-function alterations in patients with lung adenocarcinoma (LADC) in the Western world. Although they have been identified decades ago, prior efforts to target KRAS signaling with single-agent therapeutic approaches such as farnesyl transferase inhibitors, prenylation inhibition, impairment of KRAS downstream signaling, and synthetic lethality screens have been unsuccessful. Moreover, the role of KRAS oncogene in LADC is still not fully understood, and its prognostic and predictive impact with regards to the standard of care therapy remains controversial. Of note, KRASrelated studies that included general non-small cell lung cancer (NSCLC) population instead of LADC patients should be very carefully evaluated. Recently, however, comprehensive genomic profiling and wide-spectrum analysis of other co-occurring genetic alterations have identified unique therapeutic vulnerabilities. Novel targeted agents such as the covalent KRAS G12C inhibitors or the recently proposed combinatory approaches are some examples which may allow a tailored treatment for LADC patients harboring KRAS mutations. This review summarizes the current knowledge about the therapeutic approaches of KRASmutated LADC and provides an update on the most recent advances in KRAS-targeted anti-cancer strategies, with a focus on potential clinical implications.

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Section: Clinical Relevance Of Kras Mutations In Nsclcmentioning

confidence: 99%

Current therapy of KRAS-mutant lung cancer

Ghimessy

Radeczky

László

et al. 2020

Cancer Metastasis Rev

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“…KRAS mutation rate of lung adenocarcinoma is the highest in Europe followed by North America but lowest in India and China (Refs. 7 – 10 , Table 1 ). Interestingly, such geographical differences can also be found for EGFR mutation rates of lung adenocarcinoma with an opposing trend: highest in China and India and much lower in North America and Europe (Table 1 ), suggesting different carcinogenic events behind lung adenocarcinoma worldwide.…”

Section: Introductionmentioning

confidence: 99%

Molecular epidemiology and diagnostics of KRAS mutations in human cancer

Tı́már

Kashofer

2020

Cancer Metastasis Rev

203

135

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RAS mutation is the most frequent oncogenic alteration in human cancers. KRAS is the most frequently mutated followed by NRAS. The emblematic KRAS mutant cancers are pancreatic, colorectal, lung adenocarcinomas and urogenital cancers. KRAS mutation frequencies are relatively stable worldwide in various cancer types with the one exception of lung adenocarcinoma. The frequencies of KRAS variant alleles appears cancer type specific, reflecting the various carcinogenic processes. In addition to point mutation KRAS, allelic imbalances are also frequent in human cancers leading to the predominance of a mutant allele. KRAS mutant cancers are characterized by typical, cancer-type-specific co-occurring mutations and distinct gene expression signatures. The heterogeneity of KRAS mutant primary cancers is significant, affecting the variant allele frequency, which could lead to unpredictable branching development in metastases. Selection of minute mutant subclones in the primary tumors or metastases during target therapies can also occur frequently in lung or colorectal cancers leading to acquired resistance. Ultrahigh sensitivity techniques are now routinely available for diagnostic purposes, but the proper determination of mutant allele frequency of KRAS in the primary or metastatic tissues may have larger clinical significance.

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“…Recently, nucleotide-specific inhibitors of K-Ras G12C have shown promise 32 , which have fueled further efforts towards directly targeting other K-Ras mutants in active or inactive states. Such selective targeting efforts have led to comparative analyses 33 that have improved our understanding of the mutation-specific effects at both clinical [34][35][36] and molecular level [37][38][39][40][41] . For atomistic level comparative analyses, studies have utilized MD simulations to focus on the differences in the global dynamics of active and/or inactive K-Ras mutants 22,23 .…”

Section: Discussionmentioning

confidence: 99%

“…The intrinsic GTPase activity of K-Ras-GTP can be enhanced by GTPase-activating protein (GAP) binding 8,9 . A complete GTPase reaction requires well-ordered conformations of the protein active site, which includes the P-loop (residues 10-17), switch I (SI, residues [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] and switch II (SII, residues 60-74) regions (Fig 1).…”

Section: Introductionmentioning

confidence: 99%

Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras

Erman

Gümüş

2020

Preprint

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ABSTRACTK-Ras is the most frequently mutated protein in human cancers. However, until very recently, its oncogenic mutants were viewed as undruggable. To develop inhibitors that directly target oncogenic K-Ras mutants, we need to understand both their mutant-specific and pan-mutant dynamics and conformations. Recently, we have investigated how the most frequently observed K-Ras mutation in cancer patients, G12D, changes its local dynamics and conformations1. Here, we extend our analysis to study and compare the local effects of other frequently observed oncogenic mutations, G12C, G12V, G13D and Q61H. For this purpose, we have performed Molecular Dynamics (MD) simulations of each mutant when active (GTP-bound) and inactive (GDP-bound), analyzed their trajectories, and compared how each mutant changes local residue conformations, inter-protein distance distributions, local flexibility and residue pair correlated motions. Our results reveal that in the four active oncogenic mutants we have studied, the α2 helix moves closer to the C-terminal of the α3 helix. However, P-loop mutations cause α3 helix to move away from Loop7, and only G12 mutations change the local conformational state populations of the protein. Furthermore, the motions of coupled residues are mutant-specific: G12 mutations lead to new negative correlations between residue motions, while Q61H destroys them. Overall, our findings on the local conformational states and protein dynamics of oncogenic K-Ras mutants can provide insights for both mutant-selective and pan-mutant targeted inhibition efforts.

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Impact of RAS mutation subtype on clinical outcome—a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer

Cited by 42 publications

References 65 publications

Current therapy of KRAS-mutant lung cancer

Current therapy of KRAS-mutant lung cancer

Molecular epidemiology and diagnostics of KRAS mutations in human cancer

Comparative effects of oncogenic mutations G12C, G12V, G13D, and Q61H on local conformations and dynamics of K-Ras

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