The irreversible ERBB1/2/4 inhibitor neratinib interacts with the BCL-2 inhibitor venetoclax to kill mammary cancer cells.

Abstract

The irreversible ERBB1/2/4 inhibitor, neratinib, down-regulates the expression of ERBB1/2/4 as well as the levels of MCL-1 and BCL-XL. Venetoclax (ABT199) is a BCL-2 inhibitor. At physiologic concentrations neratinib interacted in a synergistic fashion with venetoclax to kill HER2 + and TNBC mammary carcinoma cells. This was associated with the drug-combination: reducing the expression and phosphorylation of ERBB1/2/3; in an eIF2α-dependent fashion reducing the expression of MCL-1 and BCL-XL and increasing the expression of Beclin1 and ATG5; and increasing the activity of the ATM-AMPKα-ULK1 S317 pathway which was causal in the formation of toxic autophagosomes. Although knock down of BAX or BAK reduced drug combination lethality, knock down of BAX and BAK did not prevent the drug combination from increasing autophagosome and autolysosome formation. Knock down of ATM, AMPKα, Beclin1 or over-expression of activated mTOR prevented the induction of autophagy and in parallel suppressed tumor cell killing. Knock down of ATM, AMPKα, Beclin1 or cathepsin B prevented the drug-induced activation of BAX and BAK whereas knock down of BID was only partially inhibitory. A 3-day transient exposure of established estrogen-independent HER2 + BT474 mammary tumors to neratinib or venetoclax did not significantly alter tumor growth whereas exposure to [neratinib + venetoclax] caused a significant 7-day suppression of growth by day 19. The drug combination neither altered animal body mass nor behavior. We conclude that venetoclax enhances neratinib lethality by facilitating toxic BH3 domain protein activation via autophagy which enhances the efficacy of neratinib to promote greater levels of cell killing.

• Authors: Laurence Booth, Jane L Roberts, Francesca Avogadri-Connors, Richard E Cutler Jr, Alshad S Lalani, Andrew Poklepovic, Paul Dent
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 19 Issue 3 Pg. 239-247 (03 04 2018) ISSN: 1555-8576 [Electronic] United States
• PMID: 29333953 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BCL2 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• Proto-Oncogene Proteins c-bcl-2
• Quinolines
• Receptors, Estrogen
• Sulfonamides
• EGFR protein, human
• ERBB2 protein, human
• ERBB4 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Receptor, ErbB-4
• neratinib
• venetoclax

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Autophagy (drug effects)
• Breast Neoplasms (drug therapy, pathology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology, therapeutic use)
• Cell Line, Tumor
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors)
• Female
• Humans
• Mice
• Mice, Nude
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Quinolines (pharmacology, therapeutic use)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Receptor, ErbB-4 (antagonists & inhibitors)
• Receptors, Estrogen (metabolism)
• Sulfonamides (pharmacology, therapeutic use)
• Treatment Outcome
• Xenograft Model Antitumor Assays