ArticleScience advances2023
Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.
Article in Science advances, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
What it found
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The trial behind it
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Who cites it
57 citing papers in PubMed, 56 citations in OpenAlex.
- Review
- Drug repurposing in KRAS G12C-mutant NSCLC: a focus on resistance mechanisms and clinical strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Acquisition of Resistance to RAS Inhibition Is Associated with the Upregulation of Macropinocytosis through Both PI3K-Dependent and -Independent Signaling.Cancer research communications · 2026Article
- RNA-triggered cell killing with CRISPR-Cas12a2.Nature · 2026Article
- Modulation of Oncogenic KRAS Signaling by Branched Actin-driven Cell Membrane Protrusions.Research square · 2026Article
- Overcoming Adaptive Resistance to KRASG12D Blockade in Pancreatic Cancer through Vertical Pathway Inhibition.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- ITGB4 up-regulated by STAT3 reduces the sensitivity of bladder cancer to cisplatin by suppressing p53.British journal of cancer · 2026Article
- Exploring genomic analysis and methylome profiling in longitudinal series of p.G12C KRAS mutated NSCLC patients treated with sotorasib.The journal of liquid biopsy · 2026Article
- Bidirectional coupling among EMT, AXL-RB1 signaling and lineage switch drives resistance to osimertinib and worse clinical outcomes in NSCLC.bioRxiv : the preprint server for biology · 2026Article
- Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer.bioRxiv : the preprint server for biology · 2026Article
- Integrating computational chemistry and machine learning to predict KRAS mutation-induced resistance.bioRxiv : the preprint server for biology · 2026Article
- Modulation of Oncogenic KRAS Signaling by Branched Actin-driven Cell Membrane Protrusions.bioRxiv : the preprint server for biology · 2026Article
- Non-enzymatic function of QSOX2 directly regulates the JUNB-ITGB4 axis and enhanced resistance to osimertinib in EGFR-mutation lung adenocarcinoma.Cell death discovery · 2026Article
- Farnesyltransferase inhibitor LB42708 disables oncogenic RAS signaling and overcomes gefitinib resistance in NSCLC via FTase α-subunit and RAS degradation.Cell communication and signaling : CCS · 2026Article
- Targeting macropinocytosis for cancer therapy.Nature reviews. Cancer · 2026Review
- Advances in targeting KRAS mutations: A promising approach for the treatment of non‑small cell lung cancer (Review).Oncology reports · 2026Review
- Tumor immune microenvironment facilitates resistance to KRAS G12C inhibitor sotorasib by altered PD-L1 expression.Journal for immunotherapy of cancer · 2026Article
- Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.Nature communications · 2026Article
- Disrupting the KRAS-SOS1 protein-protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy.Frontiers in chemistry · 2026Review
- Bioinformatics And Experimental Insights Into Sotorasib Resistance Mechanisms in Non-small-cell Lung Cancer.Anti-cancer agents in medicinal chemistry · 2026Article
Corrections and comments
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Authors and funding
35 authors at 8 institutions in 3 countries.
Funding
Abstract
Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin β4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/β-catenin signaling pathway. Thus, silencing both ITGB4 and β-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and β-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.
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Registered trials
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.