Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization

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 BRAF-mutant 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. Graphical abstract

Cancer Stem Cells and the Slow Cycling Phenotype: How to Cut the Gordian Knot Driving Resistance to Therapy in Melanoma

“…As to the first, it is widely accepted that therapy resistant slow-cycling melanoma cells are addicted to mitochondrial OXPHOS: this vulnerability represents a source of therapeutic opportunities [ 75 ]. Roesch et al firstly described through proteome profiling, which the JARID1B high subpopulation of cells upregulate several enzymes involved in mitochondrial oxidative ATP synthesis [ 55 , 72 ].…”

XXVI IMI National Congress - 1st virtual edition | 7-9 November 2020

“…1 IEO, Milan, Italy; 2 ISPRO, Florence, Italy; 3 Macquarie University, Sydney, Australia; 4 Melanoma Institute of Australia and the University of Sydney, Australia Background: Melanoma is the most aggressive form of skin cancer and is responsible for nearly 60,000 deaths globally each year. Circulating tumour DNA (ctDNA) corresponds to free fragmented DNA released by tumour cells.…”

“…Mocellin 1,2 , P. Del Fiore 1* , R. Spina 1 , A. Sommariva 5 , A. Buja 3 , A. Vecchiato 1 , F. Cavallin 4 , C.R. Rossi 1,2 , for Italian Melanoma Intergroup (IMI) 1 Surgical Oncology Unit, Veneto Institute of Oncology IOV -IRCCS, Padova Italy; 2 Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padova, Italy; 3 Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Italy; 4 Independent statistician, Solagna, Italy; 5 Veneto Institute of Oncology Institute for Hospitalization and Care Scientific, Unit of Surgical Oncology of the Esophagus and Digestive Tract Padova, Italy Background: Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited.…”

“…Sini 1 , G. Palomba 1 , M. Pisano 2 , Melanoma Unit of Sassari (MUS), Italian Association for Cancer Research (AIRC) Study Group, P.A. Ascierto 4 , C. Caracò 4 , A. Lissia 3 , A. Cossu 3 , G. Palmieri 1,2 , Italian Melanoma Intergroup (IMI)1 Istituto di Chimica Biomolecolare (ICB), Consiglio Nazionale della Ricerca (CNR), Sassari, Italy; 2 Istituto di Ricerca Genetica e Biomolecolare (IRGB), Consiglio Nazionale della Ricerca (CNR), Sassari, Italy; 3 Dipartimento di Scienze Mediche, Chirurgiche e Sperimentali, Università degli Studi di Sassari, Italy;4 Istituto Nazionale Tumori "Fondazione Pascale", Napoli, Italia Introduction: Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation testing plays a predominant role in the management of MM patients, because modern targeted therapies essentially consist of inhibitors of BRAF.…”

Nanocarrier-Based Drug Delivery for Melanoma Therapeutics

“…However, the application of anticancer drugs still have serious limitations that often compromise the effectiveness and continuity of treatment. Common chemotherapeutic agents trigger the cell breakdown by inducing DNA damage and strand breaks, interfering with DNA repair and microtubule function (especially taxanes) [ 33 , 34 ]. These chemotherapy drugs can not only kill tumor cells but also damage normal tissue cells.…”