ArticlePloS one2021
Inhibition of PI3K and MAPK pathways along with KIT inhibitors as a strategy to overcome drug resistance in gastrointestinal stromal tumors.
Article in PloS one, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 19 citations in OpenAlex.
- Targeted Therapy for Advanced Gastrointestinal Stromal Tumors: Evolution and Future Directions.Drug design, development and therapy · 2026Review
- The Mechanisms of Imatinib Resistance in Gastrointestinal Stromal Tumours: Theoretical Basis and Therapeutic Aspect.Journal of cellular and molecular medicine · 2025Review
- MITF regulates autophagy and extracellular vesicle cargo in gastrointestinal stromal tumors.Molecular biomedicine · 2025Article
- Unlocking Cellular Memory and Gene Regulatory Networks: Pioneering the Future of Therapeutic Innovations.Cells · 2025Article
- Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors.Clinical and experimental medicine · 2025Review
- SHP2 inhibition and adjuvant therapy synergistically target KIT-mutant GISTs via ERK1/2-regulated GSK3β/cyclin D1 pathway.Clinical and translational medicine · 2025Article
- Gastrointestinal stromal tumor with small cell carcinoma infiltration: a case report.Frontiers in oncology · 2024Article
- Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2023Review
- Review
- Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors.International journal of molecular sciences · 2023Review
- Review
- Microfluidic-based dynamic BH3 profiling predicts anticancer treatment efficacy.NPJ precision oncology · 2022Article
- Influence of the Microbiome Metagenomics and Epigenomics on Gastric Cancer.International journal of molecular sciences · 2022Review
- miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs.International journal of molecular sciences · 2022Article
- New treatment strategies for advanced-stage gastrointestinal stromal tumours.Nature reviews. Clinical oncology · 2022Review
- Immunosuppressive Signaling Pathways as Targeted Cancer Therapies.Biomedicines · 2022Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activating mutations in KIT/PDGFRA receptor tyrosine kinases drive gastrointestinal stromal tumors (GIST). KIT/PDGFRA inhibitors, such as imatinib do not evoke an effective cytocidal response, leaving room for quiescence and development of multiple secondary resistance mutations. As the majority of the secondary resistance clones activate PI3K and MAPK pathways, we investigated whether combined targeting of KIT/PI3K/MAPK (KPM) pathways overcomes drug resistance and quiescence in GIST cells. We monitored the proliferation of imatinib-sensitive and-resistant GIST cell lines after treating them with various combinations of drugs to inhibit KPM pathways. Cytocidal response was evaluated through proliferation, apoptosis and colony outgrowth assays. Combined inhibition of KPM signaling pathways using a KPM inhibitor cocktail decreased the survival of drug-resistant GIST cells and dramatically reduced their proliferation. Downstream pathway analysis showed that the residual PI3K/MAPK signaling observed after KIT inhibitor treatment plays a role in mediating quiescence and drug resistance. The KPM inhibitor cocktail with sunitinib or regorafenib effectively induced apoptosis and prevented colony outgrowth after long-term drug removal, suggesting that it can be used as an effective strategy against quiescence and drug resistance in metastatic GIST.
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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 Socratic graph.