Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apo
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(2020) 18:150
SHORT REPORT
Open Access
Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization Luigi Fattore1,2, Debora Malpicci3, Ciro Milite4, Sabrina Castellano4, Gianluca Sbardella4, Gerardo Botti1, Paolo A. Ascierto1, Rita Mancini5 and Gennaro Ciliberto6*
Abstract Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAFmutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy. Keywords: Melanoma, Reverse transcriptase inhibitors, Target therapy, Drug resistance, Mitochondrial membrane depolarization, DSBs
Background Combination therapy with BRAF and MEK inhibitors (MAPKi) has become standard of care for melanoma patients (approximately 50%) harboring BRAF-V600 mutations [1, 2]. This therapeutic approach results in rapid and durable objective responses in the majority of * Correspondence: [email protected] 6 IRCCS, Istituto Nazionale Tumori “Regina Elena”, Via Elio Chianesi 53, 00144 Rome, Italy Full list of author information is available at the end of the article
patients and in prolonged overall survival. A big issue, however, still remains the emergence of drug resistance [3–6]. From here, the need to identify novel and more efficient combinatorial approaches capable to control the development of drug resistant clones and to avoid disease relapse [7]. Towards this goal, our group has worked in the last years to the identification of nonmutational mechanisms involved in the acquisition of drug resistance. In this context we reported that monoclonal antibodies targeting ErbB3, a member of EGFR
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