The Multikinase Inhibitor AD80 Induces Mitotic Catastrophe and Autophagy in Pancreatic Cancer Cells

Author(s)

Lima, Keli ; de Miranda, Livia Bassani Lins ; Garnique, Anali Del Milagro Bernabe ; de Almeida, Bruna Oliveira ; do Nascimento, Mariane Cristina ; Alcantara, Guilherme Augusto Sousa ; Machado-Santelli, Glaucia Maria ; Rego, Eduardo Magalhaes ; Machado-Neto, Joao Agostinho

• Document type: Journal article
• Source: CANCERS; v. 15, n. 15, p. 14-pg., 2023-08-01.

Abstract

Simple Summary Pancreatic cancer is one of the most lethal human neoplasms, and its therapeutic repertoire remains limited. Advances in understanding the molecular complexity involved in the biology of the disease have paved the way for new therapeutic opportunities. AD80 is a multikinase inhibitor that inhibits S6K as well as RET, RAF, and SRC and displays antineoplastic effects in hematological and solid tumors. In the present study, we report the potential of AD80 as an antineoplastic agent for pancreatic cancer and the cellular and molecular changes induced by the drug. Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced & gamma;H2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease. (AU)

• FAPESP's process: 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/11606-3 - Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/12842-0 - Impact of genetic ancestry on development, molecular characteristics and clinical outcome in adult patients with Acute Lymphoblastic Leukemia
• Grantee: Keli Cristina de Lima
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 22/03316-8 - Investigation of the effects of the multikinase inhibitor AD80 in hematological neoplasms with constitutive activation of tyrosine kinase pathways
• Grantee: Lívia Bassani Lins de Miranda
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/25421-5 - Cellular and molecular evaluation of ANKHD1 silencing in breast cancer
• Grantee: Bruna Oliveira de Almeida
• Support Opportunities: Scholarships in Brazil - Scientific Initiation