ABL kinase inhibition sensitizes primary lung adenocarcinomas to chemotherapy by promoting tumor cell differentiation

The cover for issue 20 of Oncotarget features Figure 5, "Combination treatment of GNF5 and docetaxel induces cytoplasmic localization of Yap1 and decreases expression of downstream transcription targets of Yap1 compared to vehicle control treated lung adenocarcinomas," by Khatri, et al.

Non-small cell lung cancer accounts for ~80% of all lung cancer cases, and the majority of these are adenocarcinomas.

Here the authors show that ABL kinase allosteric inhibitors can be effectively used for the treatment of Kras G12D/+; p53-/- lung adenocarcinomas in an autochthonous mouse model.

Unexpectedly, the researchers found that treatment of tumor-bearing mice with an ABL allosteric inhibitor promoted differentiation of lung adenocarcinomas from poorly differentiated tumors expressing basal cell markers to tumors expressing terminal differentiation markers in vivo, which rendered lung adenocarcinomas susceptible to chemotherapy.

Dr. Ann Marie Pendergast from the Department of Pharmacology and Cancer Biology at Duke University Medical Center in Durham, NC, USA said, "With an estimated 234,000 new cases and 154,000 deaths in 2018, lung cancer is the leading cause of cancer deaths in the United States, accounting for one-quarter of all cancer deaths."

Importantly, increased ABL kinase activity has been detected in lung cancer cells without genomic alterations , and inactivation of ABL kinases suppresses lung cancer metastasis following intracardiac injection of NSCLC lines into immune-deficient mice.

Here, they demonstrate for the first time in the context of a Kras LSL-G12D; p53fl/fl mouse model of lung cancer that ABL kinase inhibition sensitizes primary lung adenocarcinomas to treatment with the chemotherapeutic agent, docetaxel.

Sensitization of lung tumors with Abl allosteric inhibitors to sub-therapeutic doses of chemotherapy would significantly decrease the deleterious side effects of chemotherapy and enhance response rates in patients with lung adenocarcinomas.

The Pendergast Research Team concluded, "Nuclear Yap1 promotes proliferative pathways in cells and translocation of Yap1 to the cytoplasm is associated with a switch from proliferative to pro-differentiation signaling.

KRAS-mutated human non-small cell lung cancers are associated with increased nuclear YAP1, and downregulation of YAP1 has been shown to synergize with the chemotherapeutic agent, cisplatin"

Full text - https://doi.org/10.18632/oncotarget.26740

Correspondence to - Ann Marie Pendergast - [email protected]

Keywords - lung adenocarcinoma, docetaxel, ABL kinases, differentiation, YAP1