ABL allosteric inhibitors synergize with statins to enhance apoptosis of metastatic lung cancer cells.

Journal Article (Journal Article)

Targeting mitochondrial metabolism has emerged as a treatment option for cancer patients. The ABL tyrosine kinases promote metastasis, and enhanced ABL signaling is associated with a poor prognosis in lung adenocarcinoma patients. Here we show that ABL kinase allosteric inhibitors impair mitochondrial integrity and decrease oxidative phosphorylation. To identify metabolic vulnerabilities that enhance this phenotype, we utilized a CRISPR/Cas9 loss-of-function screen and identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and target of statin therapies, as a top-scoring sensitizer to ABL inhibition. Combination treatment with ABL allosteric inhibitors and statins decreases metastatic lung cancer cell survival in vitro in a synergistic manner. Notably, combination therapy in mouse models of lung cancer brain metastasis and therapy resistance impairs metastatic colonization with a concomitant increase in animal survival. Thus, metabolic combination therapy might be effective to decrease metastatic outgrowth, leading to increased survival for lung cancer patients with advanced disease.

Full Text

Duke Authors

Cited Authors

  • Luttman, JH; Hoj, JP; Lin, KH; Lin, J; Gu, JJ; Rouse, C; Nichols, AG; MacIver, NJ; Wood, KC; Pendergast, AM

Published Date

  • October 2021

Published In

Volume / Issue

  • 37 / 4

Start / End Page

  • 109880 -

PubMed ID

  • 34706244

Pubmed Central ID

  • PMC8579324

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

International Standard Serial Number (ISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2021.109880

Language

  • eng