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

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178211 | GEO | 2024/04/29

REPOSITORIES: GEO

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Neuregulin 4 suppresses NASH-associated liver cancer through restraining tumor-prone liver microenvironment

Project description:The mammalian liver comprises heterogeneous cell types within its tissue microenvironment that respond to physiological cues and undergo pathophysiological reprogramming in disease states, such as nonalcoholic steatohepatitis (NASH). Patients with NASH are at increased risk for the development of hepatocellular carcinoma (HCC). However, the molecular and cellular nature of liver microenvironment remodeling that links NASH to liver carcinogenesis remains obscure. Here we show that diet-induced NASH is characterized by induction of tumor-associated macrophage (TAM)-like macrophages and exhaustion of cytotoxic T cells in mouse liver. The adipose-derived endocrine factor Neuregulin 4 (NRG4) serves as a hormonal checkpoint that restrains this pathological reprogramming during NASH. NRG4 deficiency exacerbates the induction of tumor-prone liver immune microenvironment and NASH-associated HCC, whereas transgenic NRG4 overexpression elicits protective effects in mice. In a therapeutic setting, recombinant NRG4 protein exhibits remarkable efficacy in inhibiting HCC in mice with NASH, thereby paving the way for future therapeutic development.

2022-08-15 | GSE185042 | GEO

Differential Chemoproteomics Reveals MARK2/3 as Cell Migration-Relevant Targets of the ALK Inhibitor Brigatinib

Project description:Metastasis poses a major challenge in cancer management, including EML4-ALK-rearranged non-small cell lung cancer (NSCLC). As cell migration is a critical step during metastasis, we assessed the anti-migratory activities of several clinical ALK inhibitors in NSCLC cells and observed differential anti-migratory capabilities despite similar ALK inhibition, with brigatinib displaying superior anti-migratory effects over other ALK inhibitors. Applying an unbiased in-situ mass spectrometry-based chemoproteomics approach, we determined the proteome-wide target profile of brigatinib in EML4-ALK+ NSCLC cells. Dose-dependent and cross-competitive chemoproteomics suggested MARK2 and MARK3 as relevant brigatinib kinase targets. Functional validation showed that combined pharmacological inhibition or genetic modulation of MARK2/3 inhibited cell migration. Consistently, brigatinib treatment induced inhibitory YAP1 phosphorylation downstream of MARK2/3. Collectively, our data suggest that brigatinib exhibits unusual cross-phenotype polypharmacology as despite similar efficacy for inhibiting EML4-ALK-dependent cell proliferation as other ALK inhibitors, it more effectively prevented migration of NSCLC cells due to co-targeting of MARK2/3.

2024-04-05 | PXD036716 | Pride

Fibroblast growth factor receptor 3 overexpression mediates ALK inhibitor resistance in ALK-rearranged non-small cell lung cancer

Project description:The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib, a first-generation ALK-TKI, refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counter-activated EGFR and/or Her3, and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be able to overcome by identifying precise resistance mechanisms.

2022-08-14 | GSE77764 | GEO

Differential gene expression in the colons of mice lacking neuregulin-4

Project description:Growth factors are essential for maintenance of intestinal health at homeostasis and during inflammation. We have previously shown that exogenous treatment with the growth factor neuregulin-4 (NRG4) promotes colonocyte survival during cytokine challenge and is protective in acute models of intestinal inflammation. However, the role of endogenously expressed NRG4 in colitis is not well understood. Using NRG4-/- mice, we tested the effect of endogenous NRG4 on colitis. NRG4-/- and wild type cage-mate mice were subjected to an IL-10R neutralization model of chronic colitis. NRG4-/- mice displayed reduced inflammatory cytokine expression in the colon and a reduction in tissue CD8+ T cells at 5 weeks post induction of colitis. In unchallenged NRG4-/- mice, baseline numbers of colonic CD8+ T cell numbers were unchanged. However, there was a significant decrease in splenic CD8+ T cells. RNA sequencing from colonic homogenates showed a loss of St3gal4, a sialyltransferase involved in immune cell trafficking, in the NRG4-null animals. This loss was verified in both tissue and epithelium. The regulation of St3gal4 by NRG4 was confirmed with ex vivo epithelial colon organoid cultures from NRG4-/- mice and by induction of St3gal4 in vivo following NRG4 treatment. Together our data suggest that NRG4 regulates colonic epithelial ST3GAL4 and thus the recruitment of CD8+ T cells, but also has systemic effects on T cell maturation. These effects may combine to stimulate immune mediated inflammation during IL-10R neutralization colitis.

2023-05-23 | GSE206965 | GEO

RNA-seq of human NSCLCL treated with Alectinib, Lorlatinib or Brigatinib

Project description:To better understand the differences between different ALK inhibitors on ALK positive NSCL cell lines, we performed RNA-seq analysis on samples treated with 3 types of ALK inhibitors: Alectinib, Lorlatinib and Brigatinib

2022-07-26 | E-MTAB-11342 | biostudies-arrayexpress

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

Project description:A subset of lung adenocarcinomas is driven by the EML4-ALK translocation. Despite excellent initial responses in patients, acquired resistance to ALK inhibitors occurs. Exploring these mechanisms of resistance, we found that EML4-ALK cells resistant to ALK inhibitors are remarkably sensitive to THZ1, alvocidib or dinaciclib. These compounds robustly induce apoptosis through transcriptional inhibition and downregulation of anti-apoptotic genes. In conclusion, this study shows that THZ1, alvocidib or dinaciclib could be a therapeutic option for a subset of patients with acquired resistance to first, second and third-generation ALK inhibitors.

2019-12-15 | E-MTAB-8563 | biostudies-arrayexpress

Vulnerability of drug-resistant EML4-ALK rearranged lung cancer to transcriptional inhibition

2019-12-22 | E-MTAB-8590 | biostudies-arrayexpress

RNA-seq of human NSCLC cell line treated with Tramatinib or Lorlatinib, at different time points

Project description:To better understand the differences between different ALK inhibitors on ALK positive NSCLC cell lines, we performed RNA-seq analysis on samples treated with 2 types of ALK inhibitors: Tramatinib and Lorlatinib. Samples taken 6h and 24h after treatment

2023-01-26 | E-MTAB-11834 | biostudies-arrayexpress

Proteomic analysis of genes regulated by miR-4510 in hepatocellular carcinoma

Project description:Patients with advanced hepatocellular carcinoma (HCC) are currently treated by Sorafenib and Regorafenib but efficacy of these multikinase inhibitors is disappointing. Thus, new drugs and therapies are needed to improve HCC management in clinic. We recently reported the remarkable capacity of miR-4510 to impede the growth of HCC and hepatoblastoma cells in vitro and in vivo through GPC3 targeting and Wnt pathway inactivation (Cartier F et al, Oncotarget 2017). Here, we used a label-free proteomic approach to identify new targets of miR-4510 in HCC-deriving Huh7 cells. We transfected HCC-derived Huh7 cells with either a synthetic miR-4510 mimic or a small RNA control, extracted total proteins 24hr later and comparatively analyzed proteomes of control and miR-4510-transfected cells using a quantitative label-free approach.

2019-10-23 | PXD010085 | Pride

Identification of anaplastic lymphoma kinase as a candidate of new therapeutic target for BCC

Project description:Background; Basal cell carcinoma (BCC) is the most common cancer in humans. The pathogenesis of BCC is associated with the sonic hedgehog (SHH) signaling pathway. Vismodegib, a smoothened inhibitor, that targets this pathway is now in clinical use for advanced BCC patients, but its efficacy is limited. Therefore, new therapeutic options for this cancer are required. Methods; We studied gene expression profiling of BCC tumour tissue coupled with laser capture microdissection to identify tumor specific receptor tyrosine kinase expression that can be targeted by small molecule inhibitors. The expression of selected molecules was confirmed by quantitative RT-PCR (qRT-PCR) and by immunohistochemistry. The action of kinase inhibitors was examined on primary normal human epidermal keratinocytes. Results; We found a >250 fold change increase (false discovery rate <10-4) of the oncogene, anaplastic lymphoma kinase (ALK) as well as its ligands, pleiotrophin and midkine in BCC compared to microdissected normal epidermis. qRT-PCR confirmed increased expression of ALK (p<0.05). Stronger staining of phosphorylated ALK in BCC tumour nests than normal skin was observed by immunohistochemistry. Additionally, Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation in culture, whereas a c-Met, another receptor tyrosine kinase, inhibitor did not. Crizotinib significantly reduced the expression of GLI1 and CCND2 mRNA by approximately 60% and 20%, respectively (p<0.05). Conclusions; Our data suggest that ALK may increase GLI1 expression in parallel with the conventional SHH-pathway and promotes keratinocyte proliferation. Furthermore, an ALK inhibitor alone or in combination with targeting SHH-pathway molecules may be a potential treatment for BCC patients. Laser capture microdissection was performed on 5 cases of nodular/superficial BCC, 5 cases of infiltrative BCC.

2013-01-30 | E-GEOD-42109 | biostudies-arrayexpress

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