ArticleNature communications2021
The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 44 citations in OpenAlex.
- Ligand-activated EGFR/MAPK signaling but not PI3K, are key resistance mechanisms to EGFR-therapy in colorectal cancer.Nature communications · 2025Trial
- Baseline cellular state shapes the molecular impact of mutant Kirsten rat sarcoma viral oncogene homologue (KRAS) alleles in reconstituted pancreatic cancer cells.Molecular omics · 2026Article
- HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.Science signaling · 2026Article
- Brønsted-basic small molecules activate GTP hydrolysis in KRAS-Q61 mutants.Nature chemical biology · 2026Article
- KRAS signaling networks, mutational heterogeneity, and emerging therapeutic strategies for cancer treatment.Biomarker research · 2026Review
- Precision Targeting ofInternational journal of molecular sciences · 2026Review
- SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.Journal of translational medicine · 2026Review
- Posttranslational modifications remodel proteome-wide ligandability.Nature chemical biology · 2026Article
- Translational feasibility of a plasmonic microarray-based liquid biopsy for KRAS codon mutation detection across tissue, plasma, and urine in early colorectal cancer.NPJ precision oncology · 2026Article
- The impact of K-Ras Gly12 mutants on homeostasis and tumorigenesis in the colonic epithelium.Oncogene · 2026Article
- Systematic and precise interventions for KRAS-mutant cancers.Experimental hematology & oncology · 2026Review
- CRISPR-Cas9 Screening Identifies Resistance Mechanisms to KRAS Inhibition in Pancreatic Cancer.Cancer research · 2026Article
- Lung adenocarcinoma with KRAS-Q61H: clinicopathologic features, diagnostics, and the evolving treatment landscape.Frontiers in oncology · 2026Review
- Article
- Proteomic Perspectives on KRAS-Driven Cancers and Emerging Therapeutic Approaches.Current oncology (Toronto, Ont.) · 2025Review
- Pancreatic Cells Are Resistant to KRASQ61L Expression due to Hyperactive ERK/MAPK Signaling and Apoptosis Induction.Cancer research communications · 2025Article
- Drugging the 'undruggable' KRAS: breakthroughs, challenges, and opportunities in pancreatic cancer.Cancer biology & medicine · 2025Review
- Recapitulating the adenoma-carcinoma sequence by selection of four spontaneous oncogenic mutations in mismatch-repair-deficient human colon organoids.Nature cancer · 2024Article
- Re-expression of epigenetically silenced PTPRR by histone acetylation sensitizes RAS-mutant lung adenocarcinoma to SHP2 inhibition.Cellular and molecular life sciences : CMLS · 2024Article
- Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies.Frontiers in medicine · 2024Review
Corrections and comments
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Authors and funding
22 authors at 7 institutions in 3 countries.
Funding
Abstract
Cancer cells bearing distinct KRAS mutations exhibit variable sensitivity to SHP2 inhibitors (SHP2i). Here we show that cells harboring KRAS Q61H are uniquely resistant to SHP2i, and investigate the underlying mechanisms using biophysics, molecular dynamics, and cell-based approaches. Q61H mutation impairs intrinsic and GAP-mediated GTP hydrolysis, and impedes activation by SOS1, but does not alter tyrosyl phosphorylation. Wild-type and Q61H-mutant KRAS are both phosphorylated by Src on Tyr32 and Tyr64 and dephosphorylated by SHP2, however, SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. Phosphorylation of wild-type and Gly12-mutant KRAS, which are associated with sensitivity to SHP2i, confers resistance to regulation by GAP and GEF activities and impairs binding to RAF, whereas the near-complete GAP/GEF-resistance of KRAS Q61H remains unaltered, and high-affinity RAF interaction is retained. SHP2 can stimulate KRAS signaling by modulating GEF/GAP activities and dephosphorylating KRAS, processes that fail to regulate signaling of the Q61H mutant.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.