TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors

Author(s):Show less -

de Oliveira, Erica Aparecida ^{[1, 2]} ; Chauhan, Jagat ^[1] ; da Silva, Julia Rezende ^[2] ; da Costa Carvalho, Larissa Anastacio ^[2] ; Dias, Diogo ^[1] ; de Carvalho, Danielle Goncalves ^[3] ; Masao Watanabe, Luis Roberto ^[2] ; Rebecca, Vito W. ^{[4, 5, 6]} ; Mills, Gordon ^[7] ; Lu, Yiling ^[8] ; Felipe da Silva, Aloisio Souza ^[9] ; Lopes Consolaro, Marcia Edilaine ^[10] ; Herlyn, Meenhard ^{[4, 5]} ; Possik, Patricia A. ^[3] ; Goding, Colin R. ^[1] ; Maria-Engler, Silvya Stuchi ^[2]

Affiliation

^[1] Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford - England

^[2] Univ Sao Paulo, Sch Pharmaceut Sci, Clin Chem & Toxicol Dept, Skin Biol Grp, FCF USP, Sao Paulo - Brazil

^[3] Brazilian Natl Canc Inst, Div Cellular Biol, Rio De Janeiro - Brazil

^[4] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 - USA

^[5] Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 - USA

^[6] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 - USA

^[7] Oregon Hlth & Sci Univ, Portland, OR 97201 - USA

^[8] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 - USA

^[9] Univ Sao Paulo, Univ Hosp, Dept Pathol, Anat Pathol Serv, Sao Paulo - Brazil

^[10] Univ Estadual Maringa, Dept Clin Anal & Biomed, Maringa, Parana - Brazil

• Document type: Journal article
• Source: PHARMACOLOGICAL RESEARCH; v. 173, NOV 2021.
• Web of Science Citations: 0

Abstract

In melanomas, therapy resistance can arise due to a combination of genetic, epigenetic and phenotypic mechanisms. Due to its crucial role in DNA supercoil relaxation, TOP1 is often considered an essential chemotherapeutic target in cancer. However, how TOP1 expression and activity might differ in therapy sensitive versus resistant cell types is unknown. Here we show that TOP1 expression is increased in metastatic melanoma and correlates with an invasive gene expression signature. More specifically, TOP1 expression is highest in cells with the lowest expression of MITF, a key regulator of melanoma biology. Notably, TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi- and BRAFi/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant cells with low TOP1 levels; ii) metastatic cells with high TOP1 levels and high invasiveness; and iii) BRAFi- and BRAFi/MEKi-resistant cells with low TOP1 levels and high invasiveness. Together, these results highlight the potential role of TOP1 in melanoma progression and resistance. (AU)

• FAPESP's process: 16/16554-3 - Emerging genes in melanoma progression and chemoresistance
• Grantee: Érica Aparecida de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/20665-0 - The role of ADK gene in human melanoma cells
• Grantee: Julia Rezende da Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/04926-6 - Melanoma and chemoresistance: in vitro and in silico models to exploit therapeutic targets
• Grantee: Silvya Stuchi Maria-Engler
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/14936-1 - Mitochondrial metabolism dictates the heterogeneity and resistance of melanoma
• Grantee: Larissa Anastacio da Costa Carvalho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/26148-5 - The role of TFEB/3 in response to nutrient limitation in MITF-positive and negative melanomas
• Grantee: Érica Aparecida de Oliveira
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor