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Peptides derived from the dependence receptor ALK are proapoptotic for ALK-positive tumors

A Aubry1, S Galiacy2, L Ceccato3

  • 11] Université de Toulouse, UPS, EA4555, GR2DE, CPTP, Toulouse F-31300, France [2] Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M5S 1A1, Canada.

Cell Death & Disease
|May 8, 2015
PubMed

Insights

Novel ALK-derived peptides show targeted cancer cell killing. These peptides induce apoptosis in ALK-positive tumors, offering a new therapeutic avenue against resistance to kinase inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase implicated in various human cancers.
  • Resistance to ALK inhibitors is a significant clinical challenge.
  • ALK functions as a dependence receptor, triggering apoptosis when its ligand is absent.

Purpose of the Study:

  • To develop novel ALK-targeting agents by synthesizing peptides mimicking ALK's proapoptotic domain.
  • To investigate the cytotoxic effects and mechanisms of these ALK-derived peptides on tumor cells.

Main Methods:

  • Synthesis of ALK-derived peptides, including a 36-amino acid peptide (P36).
  • Assessment of peptide cytotoxicity on ALK-positive and ALK-negative cell lines, and normal cells.
  • Analysis of apoptosis induction, caspase dependency, and N-myristoylation requirement.
  • Identification of P36-interacting proteins using surface plasmon resonance and mass spectrometry.
  • Investigation of p53 involvement via siRNA knockdown.
  • Evaluation of combination therapy with P36 and crizotinib.

Main Results:

  • The ALK-derived peptide P36 exhibited selective cytotoxicity against ALK-positive anaplastic large-cell lymphoma and neuroblastoma cell lines.
  • Cytotoxicity was mediated by caspase-dependent apoptosis and required N-myristoylation.
  • Shorter and cyclic ALK-derived peptides also induced apoptosis.
  • Interacting proteins suggested involvement of p53 signaling and pre-mRNA splicing.
  • p53 knockdown rescued cells from P36-induced apoptosis.
  • Combination therapy with P36 and crizotinib showed additive cytotoxicity.

Conclusions:

  • ALK-derived peptides, particularly P36, demonstrate potent and selective anti-tumor activity against ALK-positive malignancies.
  • These peptides induce apoptosis through caspase-dependent pathways, potentially involving p53.
  • The findings suggest that ALK-derived peptides represent a promising novel targeted therapy for ALK-positive cancers, potentially overcoming resistance mechanisms.

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