Abstract 13P
Background
Metastatic melanoma, despite recent progresses in its treatment, is still characterized by high mortality. High genomic instability found in human melanoma represents an important pathological feature, explaining high mutational burden and great response to immune checkpoint inhibitors. However, genomic instability could also represent a potential target for drugs inhibiting DNA repair mechanisms. Treatment with PARP inhibitors, alone or in combination with chemotherapy, did not show significant activity in melanoma patients. ATR (ataxia telangiectasia and Rad3 related), a protein involved in DNA repair mechanism in response to double strand breaks, is a new target in cancer therapy. Aim of this work is to evaluate the activity AZD6738, an ATR inhibitor, alone or in combination with olaparib, a PARP inhibitor, in melanoma cell lines.
Methods
Two BRAF-V600 mutant melanoma cell lines (A375 and SAN) and their in-vitro vemurafenib and cobimetinib resistant derivatives (A375-VRCR and SAN-VRCR, respectively), two NRAS mutant melanoma cell lines (SK-MEL-2 and WM1366) and one BRAF/NRAS wild type melanoma cell line (MeWo) have been treated with AZD6738, olaparib and their combination. MTT proliferation assays and colony formation assays have been performed to evaluate in-vitro activity of these drugs.
Results
MTT assays have shown that all four BRAF-V600 mutant cell lines are equally sensitive to AZD6738 (IC50: 1-1,5 μM), independently from acquired in-vitro resistance to vemurafenib and cobimetinib. Combination of AZD6738 and olaparib has shown drug synergism in all these four cell lines. This result has been confirmed in colony formation assays in which, after 240 hours exposure to the combination of AZD6738 (0,4 μM) and olaparib (2 μM), a high mortality (>94%) has been observed in all 4 cell lines, versus a low mortality (1-15%) when treated with single drugs (p<0.01). However, no synergistic activity has been found in the BRAF/NRAS wild type and the two NRAS mutant cell lines.
Conclusions
Our work has highlighted an in-vitro synergistic activity of AZD6738 and olaparib only in BRAF-V600 mutant cell lines, either naïve or with acquired in-vitro resistance to BRAF and MEK inhibitors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Dipartimento di Medicina di Precisione, Università degli Studi della Campania \"Luigi Vanvitelli\".
Funding
Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli.
Disclosure
P.P. Vitiello: Advisory/Consultancy: Biocartis. E. Martinelli: Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Merck; Advisory/Consultancy: Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Sanofi. G. Martini: Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Pfizer; Speaker Bureau/Expert testimony: Sanofi; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Speaker Bureau/Expert testimony: Servier; Advisory/Consultancy: BMS; Advisory/Consultancy: Cellgene; Advisory/Consultancy: Lilly; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Takeda. T. Troiani: Research grant/Funding (institution): Roche; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Bayer. All other authors have declared no conflicts of interest.