| First Author | Bugide S | Year | 2024 |
| Journal | iScience | Volume | 27 |
| Issue | 5 | Pages | 109800 |
| PubMed ID | 38741708 | Mgi Jnum | J:351993 |
| Mgi Id | MGI:7640985 | Doi | 10.1016/j.isci.2024.109800 |
| Citation | Bugide S, et al. (2024) ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models. iScience 27(5):109800 |
| abstractText | 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. |
