ArticleCancer research2022
A Genome-Wide Screen Identifies PDPK1 as a Target to Enhance the Efficacy of MEK1/2 Inhibitors in NRAS Mutant Melanoma.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 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
18 citing papers in PubMed, 25 citations in OpenAlex.
- In vivo CRISPR knockout screen identifies Polr1a as a key driver and a potential therapeutic target for melanoma metastasis.Oncogene · 2026Article
- Harnessing pyroptosis to restrain melanoma through aripiprazole.Apoptosis : an international journal on programmed cell death · 2026Article
- Melanoma: Pathogenesis and Targeted Therapy.MedComm · 2026Review
- Transcriptomic insights into GSDME-driven pyroptosis in head and neck cancer.Scientific reports · 2025Article
- Review
- Mechanistic role of miR-375 in regulating PDPK1 to promote progression of small bowel neuroendocrine tumors: a silico analysis.Discover oncology · 2025Article
- Review
- Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer.Nature chemical biology · 2025Article
- Targeting ferroptosis, pyroptosis and necroptosis for cancer immunotherapy in melanoma: mechanistic insights and clinical perspectives.Frontiers in immunology · 2025Review
- Melanoma biology and treatment: a review of novel regulated cell death-based approaches.Cancer cell international · 2024Review
- Multiomics characterization of pyroptosis in the tumor microenvironment and therapeutic relevance in metastatic melanoma.BMC medicine · 2024Article
- Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B-cell lymphomas.Cancer science · 2023Article
- Harnessing the Potential of Non-Apoptotic Cell Death Processes in the Treatment of Drug-Resistant Melanoma.International journal of molecular sciences · 2023Review
- The Therapeutic Potential of Pyroptosis in Melanoma.International journal of molecular sciences · 2023Review
- Application of CRISPR screen in mechanistic studies of tumor development, tumor drug resistance, and tumor immunotherapy.Frontiers in cell and developmental biology · 2023Review
- The Emerging Burden of Genetic Instability and Mutation in Melanoma: Role of Molecular Mechanisms.Cancers · 2022Article
- Identification ofBiology · 2022Article
- Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies.Cancers · 2022Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Melanomas frequently harbor activating NRAS mutations. However, limited advance has been made in developing targeted therapy options for patients with NRAS mutant melanoma. MEK inhibitors (MEKi) show modest efficacy in the clinic and their actions need to be optimized. In this study, we performed a genome-wide CRISPR-Cas9-based screen and demonstrated that loss of phosphoinositide-dependent kinase-1 (PDPK1) enhances the efficacy of MEKi. The synergistic effects of PDPK1 loss and MEKi was validated in NRAS mutant melanoma cell lines using pharmacologic and molecular approaches. Combined PDPK1 inhibitors (PDPK1i) with MEKi suppressed NRAS mutant xenograft growth and induced gasdermin E-associated pyroptosis. In an immune-competent allograft model, PDPK1i+MEKi increased the ratio of intratumoral CD8+ T cells, delayed tumor growth, and prolonged survival; the combination treatment was less effective against tumors in immune-deficient mice. These data suggest PDPK1i+MEKi as an efficient immunostimulatory strategy against NRAS mutant melanoma. SIGNIFICANCE: Targeting PDPK1 stimulates antitumor immunity and sensitizes NRAS mutant melanoma to MEK inhibition, providing rationale for the clinical development of a combinatorial approach for treating patients with melanoma.
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What Socratic holds
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.