ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models

Suresh Bugide; Dhana Sekhar Reddy; Parmanand Malvi; Romi Gupta; Narendra Wajapeyee

doi:10.1016/j.isci.2024.109800

ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models

iScience. 2024 Apr 23;27(5):109800. doi: 10.1016/j.isci.2024.109800. eCollection 2024 May 17.

Authors

Suresh Bugide¹, Dhana Sekhar Reddy¹, Parmanand Malvi¹, Romi Gupta^{1

2}, Narendra Wajapeyee^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
² O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.

Abstract

Hepatocellular carcinoma (HCC) currently lacks effective therapies, leaving a critical need for new treatment options. A previous study identified the anaplastic lymphoma kinase (ALK) amplification in HCC patients, raising the question of whether ALK inhibitors could be a viable treatment. Here, we showed that both ALK inhibitors and ALK knockout effectively halted HCC growth in cell cultures. Lorlatinib, a potent ALK inhibitor, suppressed HCC tumor growth and metastasis across various mouse models. Additionally, in an advanced immunocompetent humanized mouse model, when combined with an anti-PD-1 antibody, lorlatinib more potently suppressed HCC tumor growth, surpassing individual drug efficacy. Lorlatinib induced apoptosis and senescence in HCC cells, and the senolytic agent ABT-263 enhanced the efficacy of lorlatinib. Additional studies identified that the apoptosis-inducing effect of lorlatinib was mediated via GGN and NRG4. These findings establish ALK inhibitors as promising HCC treatments, either alone or in combination with immunotherapies or senolytic agents.

Keywords: Biological sciences; Cancer; Cancer systems biology; Natural sciences; Pharmacology; Systems biology.