ArticleOncotarget2016
Acquired savolitinib resistance in non-small cell lung cancer arises via multiple mechanisms that converge on MET-independent mTOR and MYC activation.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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
24 citing papers in PubMed, 37 citations in OpenAlex.
- Parent and Metabolite Concentration-QT Modeling to Evaluate QT-Interval Prolongation at Savolitinib Therapeutic Doses.The AAPS journal · 2021Trial
- Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer.Respiratory research · 2026Article
- MYC contributes to targeted therapy resistance in lung cancers driven by MET exon 14-skipping alteration.NPJ precision oncology · 2026Article
- Review
- Combining mechanistic quantitative systems pharmacology modeling and patient-derived organoid testing in MET-aberrant non-small cell lung cancer for high-throughput combination efficacy analysis and personalized treatment design.Frontiers in pharmacology · 2025Article
- DGDRP: drug-specific gene selection for drug response prediction via re-ranking through propagating and learning biological network.Frontiers in genetics · 2024Article
- Patient-derived exosomes facilitate therapeutic targeting of oncogenic MET in advanced gastric cancer.Science advances · 2023Article
- Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B.Cell reports. Medicine · 2023Article
- Savolitinib: A Promising Targeting Agent for Cancer.Cancers · 2023Review
- Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model.Molecular cancer therapeutics · 2023Article
- Dramatic response and acquired resistance to savolitinib in advanced intrahepatic cholangiocarcinoma with MET amplification: a case report and literature review.Frontiers in oncology · 2023Article
- Landscape of Savolitinib Development for the Treatment of Non-Small Cell Lung Cancer with MET Alteration-A Narrative Review.Cancers · 2022Review
- MET Exon 14 Splice-Site Mutations Preferentially Activate KRAS Signaling to Drive Tumourigenesis.Cancers · 2022Article
- SRC and PIM1 as potential co-targets to overcome resistance in MET deregulated non-small cell lung cancer.Translational lung cancer research · 2020Article
- Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells.Oncotarget · 2020Article
- Review
- PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer.Signal transduction and targeted therapy · 2020Review
- Targeting the HGF/MET Axis in Cancer Therapy: Challenges in Resistance and Opportunities for Improvement.Frontiers in cell and developmental biology · 2020Review
- Review
- Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy.Nature reviews. Cancer · 2018Review
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lung cancer is the most common cause of cancer death globally with a significant, unmet need for more efficacious treatments. The receptor tyrosine kinase MET has been implicated as an oncogene in numerous cancer subtypes, including non-small cell lung cancer (NSCLC). Here we explore the therapeutic potential of savolitinib (volitinib, AZD6094, HMPL-504), a potent and selective MET inhibitor, in NSCLC. In vitro, savolitinib inhibits MET phosphorylation with nanomolar potency, which correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo, savolitinib causes inhibition of these pathways and significantly decreases growth of MET-dependent xenografts. To understand resistance mechanisms, we generated savolitinib resistance in MET-amplified NSCLC cell lines and analyzed individual clones. We found that upregulation of MYC and constitutive mTOR pathway activation is a conserved feature of resistant clones that can be overcome by knockdown of MYC or dual mTORC1/2 inhibition. Lastly, we demonstrate that mechanisms of resistance are heterogeneous, arising via a switch to EGFR dependence or by a requirement for PIM signaling. This work demonstrates the efficacy of savolitinib in NSCLC and characterizes acquired resistance, identifying both known and novel mechanisms that may inform combination strategies in the clinic.
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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.