Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma

Autor(es):Mostrar menos -

Rebecca, Vito W. ^[1] ; Massaro, Renato R. ^[2] ; Fedorenko, Inna V. ^[1] ; Sondak, Vernon K. ^[3] ; Anderson, Alexander R. A. ^[4] ; Kim, Eunjung ^[4] ; Amaravadi, Ravi K. ^[5] ; Maria-Engler, Silvya S. ^[2] ; Messina, Jane L. ^{[3, 6]} ; Gibney, Geoffrey T. ^[3] ; Kudchadkar, Ragini R. ^[3] ; Smalley, Keiran S. M. ^{[3, 1]}

Afiliação do(s) autor(es)

^[1] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL 33612 - USA

^[2] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Anal & Toxicol, Sao Paulo - Brazil

^[3] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Cutaneous Oncol, Tampa, FL 33612 - USA

^[4] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Dept Integrated Math Oncol, Tampa, FL 33612 - USA

^[5] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 - USA

^[6] Univ South Florida Coll Med, Dept Pathol & Cell Biol, Tampa, FL - USA

• Tipo de documento: Artigo Científico
• Fonte: PIGMENT CELL & MELANOMA RESEARCH; v. 27, n. 3, p. 465-478, MAY 2014.
• Citações Web of Science: 27

Resumo

This study investigates the mechanism of action behind the long-term responses (12-16months) of two BRAFWT melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. Although single agent MK-2206 inhibited phospho-AKT signaling, it did not impact in vitro melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin was cytotoxic in long-term colony formation and 3D spheroid assays, and induced autophagy. Autophagy was initially protective with autophagy inhibitors and deletion of ATG5 found to enhance cytotoxicity. Although prolonged autophagy induction (>6days) led to caspase-dependent apoptosis, drug resistant clones still emerged. Autophagy inhibition enhanced the cell death response through reactive oxygen species and could be reversed by anti-oxidants. We demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAFWT melanoma and show that an autophagy inhibitor may prevent resistance to these drugs. (AU)

• Processo FAPESP: 10/50300-2 - Efeito do resveratrol e do 2-metoxiestradiol em linhagens de melanoma humano em modelos de monocamada e de pele reconstituida.
• Beneficiário: Renato Ramos Massaro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/05732-7 - Efeito do 2-metoxiestradiol na citotoxicidade e quimiorresistência de linhagens de melanoma humano
• Beneficiário: Renato Ramos Massaro
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado