ArticleCell reports. Medicine2022
Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer.
Article in Cell reports. Medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Aptamer-based inhibition of MNK1 reduces pancreatic ductal adenocarcinoma growth by targeting cancer stem cells.Journal of biomedical science · 2026Article
- SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.Journal of translational medicine · 2026Review
- CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations.Signal transduction and targeted therapy · 2026Article
- Inhibition, But Not Depletion, of Erk Signaling Ameliorates Anthracycline-Induced Cardiotoxicity in Zebrafish.JACC. CardioOncology · 2025Article
- RAS Pathway Inhibitors Combined with Targeted Agents Are Active in Patient-Derived Spheroids with Oncogenic KRAS Variants from Multiple Cancer Types.Cancer research communications · 2025Article
- Article
- A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy.Signal transduction and targeted therapy · 2025Article
- KRASMolecular oncology · 2025Article
- Functional screening reveals genetic dependencies and diverging cell cycle control in atypical teratoid rhabdoid tumors.Genome biology · 2024Article
- Pancreatic Cancer: Current Concepts, Trends, and Future Directions.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2024Review
- Review
- Combinatorial strategies to target RAS-driven cancers.Nature reviews. Cancer · 2024Review
- Biological and targeting differences between the rare KRAS A146T and canonical KRAS mutants in gastric cancer models.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2024Article
- Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives.International journal of molecular sciences · 2024Review
- Tyrosine phosphataseFrontiers in immunology · 2024Review
- The current landscape of using direct inhibitors to target KRASExperimental hematology & oncology · 2023Review
- Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope (Review).Oncology reports · 2023Review
- SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment.Cancer discovery · 2023Review
- Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.Signal transduction and targeted therapy · 2023Review
Corrections and comments
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Authors and funding
24 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that
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