SynthesisJournal of experimental & clinical cancer research : CR2022
The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer.
Synthesis in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 24 citations in OpenAlex.
- Regulation of Amino Acid Transporters by Cell Surface Receptors.Antioxidants (Basel, Switzerland) · 2026Review
- Tertiary lymphoid structure-related genes drive tumor microenvironment heterogeneity and prognostic disparities in left-Translational cancer research · 2026Article
- Organoids glimpse: the nexus for diverse tumor heterogeneity.Frontiers in cell and developmental biology · 2026Review
- A humanized anaplastic lymphoma kinase (ALK)-directed antibody-drug conjugate with pyrrolobenzodiazepine payload demonstrates efficacy in ALK-expressing cancers.Nature communications · 2025Article
- Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- CCN1 is a therapeutic target upregulated in EML4-ALK mutant lung adenocarcinoma reversibly resistant to alectinib.Cell death & disease · 2025Article
- Large-scale analysis of cell-cell communication reveals angiogenin-dependent tumor progression in clear cell renal cell carcinoma.iScience · 2023Article
- Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex.Journal of experimental & clinical cancer research : CR · 2023Article
- Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review.Biomolecules · 2023Review
- LTK and ALK promote neuronal polarity and cortical migration by inhibiting IGF1R activity.EMBO reports · 2023Article
- Principles of Molecular Utility for CMS Classification in Colorectal Cancer Management.Cancers · 2023Review
- Genome-wide screening for differentially methylated long noncoding RNAs identifies LIFR-AS1 as an epigenetically regulated lncRNA that inhibits the progression of colorectal cancer.Clinical epigenetics · 2022Article
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Authors and funding
19 authors at 8 institutions in 3 countries.
Funding
Abstract
backgroundIn the last years, several efforts have been made to classify colorectal cancer (CRC) into well-defined molecular subgroups, representing the intrinsic inter-patient heterogeneity, known as Consensus Molecular Subtypes (CMSs).
methodsIn this work, we performed a meta-analysis of CRC patients stratified into four CMSs. We identified a negative correlation between a high level of anaplastic lymphoma kinase (ALK) expression and relapse-free survival, exclusively in CMS1 subtype. Stemming from this observation, we tested cell lines, patient-derived organoids and mice with potent ALK inhibitors, already approved for clinical use.
resultsALK interception strongly inhibits cell proliferation already at nanomolar doses, specifically in CMS1 cell lines, while no effect was found in CMS2/3/4 groups. Furthermore, in vivo imaging identified a role for ALK in the dynamic formation of 3D tumor spheroids. Consistently, ALK appeares constitutively phosphorylated in CMS1, and it signals mainly through the AKT axis. Mechanistically, we found that CMS1 cells display several copies of ALKAL2 ligand and ALK-mRNAs, suggesting an autocrine loop mediated by ALKAL2 in the activation of ALK pathway, responsible for the invasive phenotype. Consequently, disruption of ALK axis mediates the pro-apoptotic action of CMS1 cell lines, both in 2D and 3D and enhanced cell-cell adhesion and e-cadherin organization. In agreement with all these findings, the ALK signature encompassing 65 genes statistically associated with worse relapse-free survival in CMS1 subtype. Finally, as a proof of concept, the efficacy of ALK inhibition was demonstrated in both patient-derived organoids and in tumor xenografts in vivo.
conclusionsCollectively, these findings suggest that ALK targeting may represent an attractive therapy for CRC, and CMS classification may provide a useful tool to identify patients who could benefit from this treatment. These findings offer rationale and pharmacological strategies for the treatment of CMS1 CRC.
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