2. Academic Validation
  3. The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer

The autocrine loop of ALK receptor and ALKAL2 ligand is an actionable target in consensus molecular subtype 1 colon cancer

  • J Exp Clin Cancer Res. 2022 Mar 29;41(1):113. doi: 10.1186/s13046-022-02309-1.
Martina Mazzeschi  # 1,  Michela Sgarzi  # 1,  Donatella Romaniello 1,  Valerio Gelfo 1,  Carola Cavallo 2,  Francesca Ambrosi 3,  Alessandra Morselli 1,  Carmen Miano 4,  Noemi Laprovitera 1,  Cinzia Girone 1,  Manuela Ferracin 1,  Spartaco Santi 5 6,  Karim Rihawi 7,  Andrea Ardizzoni 1 7,  Michelangelo Fiorentino 1,  Gabriele D'Uva 1 4,  Balázs Győrffy 8 9,  Ruth Palmer 10,  Mattia Lauriola 11 12
Affiliations

Affiliations

  • 1 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
  • 2 Laboratory of Preclinical Studies for Regenerative Medicine of the Musculoskeletal System (RAMSES), (IRCCS) Istituto Ortopedico Rizzoli, Bologna, Italy.
  • 3 Pathology Unit, Maggiore Hospital, AUSL Bologna, Bologna, Italy.
  • 4 National Laboratory of Molecular Biology and Stem Cell Engineering, National Institute of Biostructures and Biosystems (INBB), Bologna, Italy.
  • 5 Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy.
  • 6 IRCCS-Institute Orthopaedic Rizzoli, Bologna, Italy.
  • 7 Medical Oncology, IRCSS Azienda-Ospedaliero Universitaria di Bologna, Via Albertoni 15, 40138, Bologna, Italy.
  • 8 Semmelweis University Department of Bioinformatics and 2nd Department Of Pediatrics, Budapest, Hungary.
  • 9 TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
  • 10 Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 11 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy. mattia.lauriola2@unibo.it.
  • 12 Centre for Applied Biomedical Research (CRBA), Bologna University Hospital Authority St. Orsola -Malpighi Polyclinic, Via Belmeloro 8, 40125, Bologna, Italy. mattia.lauriola2@unibo.it.
  • # Contributed equally.
PMID: 35351152 DOI: 10.1186/s13046-022-02309-1
Abstract

Background: In 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).

Methods: In 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.

Results: ALK 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.

Conclusions: Collectively, 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.

Keywords

3D; AKT; ALK; ALKAL2; CMS1; Colon Cancer therapy; Signalling.

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