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| Status |
Public on Apr 29, 2024 |
| Title |
ALK inhibitors suppress HCC and synergize with anti-PD-1 therapy and ABT-263 in preclinical models |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
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| Overall design |
Total RNA was extracted from all non target expressing and ALK targeted inhibition in HepG2, SK-HEP1 and SNU449 cells, followed by poly-A selection and RNA-sequencing using Illumina Hi-Seq 2500 platform, with three biological replicates for each transformed sample.
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| Contributor(s) |
Bugide S, Reddy D, Malvi P, Gupta R, Wajapeyee N |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Jun 15, 2021 |
| Last update date |
Apr 29, 2024 |
| Contact name |
Narendra Wajapeyee |
| E-mail(s) |
nwajapey@uab.edu
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| Phone |
205-934-5331
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| Organization name |
University of Alabama at Birmingham
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| Department |
Department of Biochemistry and Molecular Genetics
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| Street address |
720 20th Street South, Kaul 540A
|
| City |
Birmingham |
| State/province |
AL |
| ZIP/Postal code |
35233 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL21290 |
Illumina HiSeq 3000 (Homo sapiens) |
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| Samples (18)
|
| GSM5384469 |
HepG2/C3A Non-Target Expressing cells (Replicate_1) |
| GSM5384470 |
HepG2/C3A Non-Target Expressing cells (Replicate_2) |
| GSM5384471 |
HepG2/C3A Non-Target Expressing cells (Replicate_3) |
| GSM5384472 |
HepG2/C3A ALK targeted inhibition cells (Replicate_1) |
| GSM5384473 |
HepG2/C3A ALK targeted inhibition cells (Replicate_2) |
| GSM5384474 |
HepG2/C3A ALK targeted inhibition cells (Replicate_3) |
| GSM5384475 |
SK-HEP1 Non-Target Expressing cells (Replicate_1) |
| GSM5384476 |
SK-HEP1 Non-Target Expressing cells (Replicate_2) |
| GSM5384477 |
SK-HEP1 Non-Target Expressing cells (Replicate_3) |
| GSM5384478 |
SK-HEP1 ALK targeted inhibition cells (Replicate_1) |
| GSM5384479 |
SK-HEP1 ALK targeted inhibition cells (Replicate_2) |
| GSM5384480 |
SK-HEP1 ALK targeted inhibition cells (Replicate_3) |
| GSM5384481 |
SNU-449 Non-Target Expressing cells (Replicate_1) |
| GSM5384482 |
SNU-449 Non-Target Expressing cells (Replicate_2) |
| GSM5384483 |
SNU-449 Non-Target Expressing cells (Replicate_3) |
| GSM5384484 |
SNU-449 ALK targeted inhibition cells (Replicate_1) |
| GSM5384485 |
SNU-449 ALK targeted inhibition cells (Replicate_2) |
| GSM5384486 |
SNU-449 ALK targeted inhibition cells (Replicate_3) |
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| Relations |
| BioProject |
PRJNA737761 |
| SRA |
SRP324103 |
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