ArticleMolecular carcinogenesis2017
P21-activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells.
Article in Molecular carcinogenesis, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 35 citations in OpenAlex.
- Targeted therapy in BRAF‑mutant melanoma: Advances and challenges (Review).International journal of oncology · 2026Review
- Inhibitors of De Novo Guanylate Biosynthesis Enhance the Potency of MAPK Cascade Inhibitors Against Colorectal Cancer.International journal of molecular sciences · 2025Article
- A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition.Oncogene · 2025Article
- Inhibition of the RAC/PAK Signaling Axis Enhances the Potency of MAPK Cascade Inhibitors Against Uveal Melanoma.Biomolecules · 2025Article
- A novel PAK1/TCF1 regulatory axis promotes non-small cell lung cancer progression.Discover oncology · 2025Article
- Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- PAK1 and Therapy Resistance in Melanoma.Cells · 2023Review
- Hyperactivation of p21-Activated Kinases in Human Cancer and Therapeutic Sensitivity.Biomedicines · 2023Review
- Immune Checkpoint Inhibitors and RAS-ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma.Biomolecules · 2022Review
- PAK6 promotes homologous-recombination to enhance chemoresistance to oxaliplatin through ATR/CHK1 signaling in gastric cancer.Cell death & disease · 2022Article
- p21-Activated kinases as promising therapeutic targets in hematological malignancies.Leukemia · 2022Review
- Proteotoxic Stress as an Exploitable Vulnerability in Cells with Hyperactive AKT.International journal of molecular sciences · 2021Article
- Blockage of PAK1 alleviates the proliferation and invasion of NSCLC cells via inhibiting ERK and AKT signaling activity.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2021Article
- Review
- Coordinated dysregulation of cancer progression by the HER family and p21-activated kinases.Cancer metastasis reviews · 2020Review
- p21-Activated Kinases in Thyroid Cancer.Endocrinology · 2020Review
- P21-Activated Kinase 1: Emerging biological functions and potential therapeutic targets in Cancer.Theranostics · 2020Review
- IODVA1, a guanidinobenzimidazole derivative, targets Rac activity and Ras-driven cancer models.PloS one · 2020Article
- The role of polo-like kinase 3 in the response of BRAF-mutant cells to targeted anticancer therapies.Molecular carcinogenesis · 2020Article
- MAPK- and AKT-activated thyroid cancers are sensitive to group I PAK inhibition.Endocrine-related cancer · 2019Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
BRAF is a commonly mutated oncogene in various human malignancies and a target of a new class of anti-cancer agents, BRAF-inhibitors (BRAFi). The initial enthusiasm for these agents, based on the early successes in the management of metastatic melanoma, is now challenged by the mounting evidence of intrinsic BRAFi-insensitivity in many BRAF-mutated tumors, by the scarcity of complete responses, and by the inevitable emergence of drug resistance in initially responsive cases. These setbacks put an emphasis on discovering the means to increase the efficacy of BRAFi and to prevent or overcome BRAFi-resistance. We explored the role of p21-activated kinases (PAKs), in particular PAK1, in BRAFi response. BRAFi lowered the levels of active PAK1 in treated cells. An activated form of PAK1 conferred BRAFi-resistance on otherwise sensitive cells, while genetic or pharmacologic suppression of PAK1 had a sensitizing effect. While activation of AKT1 and RAC1 proto-oncogenes increased BRAFi-tolerance, the protective effect was negated in the presence of PAK inhibitors. Furthermore, combining otherwise ineffective doses of PAK- and BRAF-inhibitors synergistically affected intrinsically BRAFi-resistant cells. Considering the high incidence of PAK1 activation in cancers, our findings suggests PAK inhibition as a strategy to augment BRAFi therapy and overcome some of the well-known resistance mechanisms.
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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.