Banca de DEFESA: LAURA FRANCISCA LEITE DO PRADO DE SOUZA
Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.STUDENT : LAURA FRANCISCA LEITE DO PRADO DE SOUZA
DATE: 07/08/2023
TIME: 14:00
LOCAL: Sala 307 do Bloco B do Campus de Santo André da Universidade Federal do ABC
TITLE:
Modulation of MAPK/ERK signaling pathway by vemurafenib in NRASQ61R-mutated melanoma and its effects on mitochondrial dynamics
PAGES: 85
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUBÁREA: Metabolismo e Bioenergética
SUMMARY:
Melanoma is the deadliest type of skin cancer. About 40-50% of cases of cutaneous melanoma present a mutation in the BRAF gene and 15-20% in the NRAS gene. Such mutations constitutively activate the MAPK/ERK signaling pathway, which accounts for cell proliferation and survival. Targeted therapy using MAPK/ERK signaling inhibitors has revolutionized melanoma treatment. Currently, there are inhibitors for mutated BRAF to block MAPK/ERK signaling, but no NRAS inhibitor. Vemurafenib was the first FDA-approved targeted therapy drug, it prolongs survival in patients with unresectable metastatic melanoma or BRAFV600E-mutated melanoma. However, if used in patients with the NRAS mutation or without the BRAF mutation (wildtype), vemurafenib increases the signaling of the MAPK/ERK pathway through paradoxical activation, worsening the patients’ prognosis. Also, previous studies suggested that vemurafenib resistance in BRAF mutated melanoma arises due to secondary mutations in NRAS, and changes in mitochondrial energy processes also seem to be involved. Considering that mitochondria constantly fuse or divide in order to adapt to the metabolic demands of the cell, and that a previous study showed that vemurafenib induces mitochondrial fusion in BRAF mutated melanoma, the aim of this study was to study changes in mitochondrial dynamics induced by vemurafenib in melanoma cells with NRASQ61R mutation (SK-MEL-147) and how the modulation of this process can sensitize these cells to the action of vemurafenib. Our results showed that vemurafenib promoted the paradoxical activation of the MAPK/ERK pathway in SK-MEL-147 cells. Furthermore, unlike mutated BRAF cells, extensive mitochondrial fusion was not observed in mutated NRAS cells, with mitochondrial fission morphology prevailing, i.e., smaller and rounded mitochondria. Since DRP-1 (dynamin related protein 1) plays a central role in the process of mitochondrial fission, we used an inhibitor of its activation. Thus, the inhibition of DRP-1 by mdivi-1 was able to sensitize mutated NRAS cells to vemurafenib. These results contribute to the understanding of the molecular mechanisms associated with the paradoxical activation of the MAPK/ERK pathway by vemurafenib in melanoma cells with the NRASQ61R mutation and point to mitochondria as a potential target for combination chemotherapy in this type of cancer.
COMMITTEE MEMBERS:
Presidente - Interno ao Programa - 1674592 - TIAGO RODRIGUES
Membro Titular - Examinador(a) Interno ao Programa - 1227329 - CESAR AUGUSTO JOAO RIBEIRO
Membro Titular - Examinador(a) Externo ao Programa - 3298750 - ANA CLAUDIA OLIVEIRA CARREIRA NISHIYAMA
Membro Suplente - Examinador(a) Externo à Instituição - IVARNE LUIS DOS SANTOS TERSARIAL - UNIFESP