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Ref Type Journal Article
PMID (37729428)
Authors Ferretti LP, Böhi F, Leslie Pedrioli DM, Cheng PF, Ferrari E, Baumgaertner P, Alvarado-Diaz A, Sella F, Cereghetti A, Turko P, Wright RH, De Bock K, Speiser DE, Ferrari R, Levesque MP, Hottiger MO
Title Combinatorial Treatment with PARP and MAPK Inhibitors Overcomes Phenotype Switch-Driven Drug Resistance in Advanced Melanoma.
URL
Abstract Text Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors (MAPKi). A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of patients with melanoma. Using a drug screen targeting chromatin regulators in patient-derived three-dimensional MAPKi-resistant melanoma cell cultures, we discovered that PARP inhibitors (PARPi) restore sensitivity to MAPKis, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARPis induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed epithelial-mesenchymal transition-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPKi-sensitive state. The combination of PARP and MAPKis synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating patients with melanoma with PARPis in combination with MAPKis to abrogate acquired therapy resistance.PARP inhibitors can overcome resistance to MAPK inhibitors by activating autophagic cell death and reversing phenotype switching, suggesting that this synergistic combination could help improve the prognosis of patients with melanoma.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E NRAS Q61K melanoma sensitive Encorafenib + Rucaparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Rubraca (rucaparib) and Braftovi (encorafenib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61K in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61H melanoma sensitive Binimetinib + Encorafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib), Braftovi (encorafenib), and Mektovi (binimetinib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61H in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61R melanoma sensitive Binimetinib + Encorafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib) Braftovi (encorafenib), and Mektovi (binimetinib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61R in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61R melanoma predicted - sensitive Dabrafenib + Trametinib Preclinical - Pdx Actionable In a preclinical study, treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) moderately inhibited tumor growth in a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61R (PMID: 37729428). 37729428
BRAF V600E NRAS Q61K melanoma resistant Dabrafenib Preclinical - Pdx Actionable In a preclinical study, a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61K was resistant to treatment with Tafinlar (dabrafenib) (PMID: 37729428). 37729428
BRAF V600E NRAS Q61K melanoma sensitive Talazoparib Preclinical - Pdx Actionable In a preclinical study, Talzenna (talazoparib) treatment inhibited tumor growth and led to improved survival compared to controls in a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61K (PMID: 37729428). 37729428
BRAF V600E NRAS Q61R melanoma resistant Dabrafenib Preclinical - Pdx Actionable In a preclinical study, a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61R was resistant to treatment with Tafinlar (dabrafenib) (PMID: 37729428). 37729428
BRAF V600E NRAS Q61R melanoma sensitive Dabrafenib + Talazoparib + Trametinib Preclinical - Pdx Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib), Tafinlar (dabrafenib), and Mekinist (trametinib) inhibited tumor growth and improved survival compared to controls in a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61R (PMID: 37729428). 37729428
BRAF V600E NRAS Q61K melanoma sensitive Dabrafenib + Talazoparib + Trametinib Preclinical - Pdx Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib), Tafinlar (dabrafenib), and Mekinist (trametinib) inhibited tumor growth and improved survival compared to controls in a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61K (PMID: 37729428). 37729428
BRAF V600E NRAS Q61R melanoma sensitive Encorafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib) and Braftovi (encorafenib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61R in culture (PMID: 37729428). 37729428
BRAF V600E melanoma sensitive Encorafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib) and Braftovi (encorafenib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61H melanoma sensitive Encorafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib) and Braftovi (encorafenib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61H in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61K melanoma sensitive Encorafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib) and Braftovi (encorafenib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61K in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61R melanoma sensitive Talazoparib Preclinical - Pdx Actionable In a preclinical study, Talzenna (talazoparib) treatment inhibited tumor growth and led to improved survival compared to controls in a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61R (PMID: 37729428). 37729428
BRAF V600E NRAS Q61K melanoma sensitive Dabrafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib) and Tafinlar (dabrafenib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61K in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61R melanoma resistant Trametinib Preclinical - Pdx Actionable In a preclinical study, a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61R was resistant to treatment with Mekinist (trametinib) (PMID: 37729428). 37729428
BRAF V600E melanoma sensitive Binimetinib + Encorafenib + Talazoparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Talzenna (talazoparib), Braftovi (encorafenib), and Mektovi (binimetinib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E in culture (PMID: 37729428). 37729428
BRAF V600E NRAS Q61K melanoma sensitive Dabrafenib + Trametinib Preclinical - Pdx Actionable In a preclinical study, treatment with the combination of Tafinlar (dabrafenib) and Mekinist (trametinib) moderately inhibited tumor growth in a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and NRAS Q61K (PMID: 37729428). 37729428
BRAF V600E NRAS Q61K melanoma sensitive Encorafenib + Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, treatment with the combination of Lynparza (olaparib) and Braftovi (encorafenib) synergistically inhibited viability of patient-derived melanoma spheroids harboring BRAF V600E and NRAS Q61K in culture (PMID: 37729428). 37729428