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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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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 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 | 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 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 | 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 | 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 | 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 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 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 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 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 | 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 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 |
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 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 + 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 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 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 | 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 |