Abstract
ALK is a receptor tyrosine kinase, associated with many tumor types as diverse as anaplastic large cell lymphomas, inflammatory myofibroblastic tumors, breast and renal cell carcinomas, non-small cell lung cancer, neuroblastomas, and more. This makes ALK an attractive target for cancer therapy. Since ALK–driven tumors are dependent for their proliferation on the constitutively activated ALK kinase, a number of tyrosine kinase inhibitors have been developed to block tumor growth. While some inhibitors are under investigation in clinical trials, others are now approved for treatment, notably in ALK-positive lung cancer. Their efficacy is remarkable, however limited in time, as the tumors escape and become resistant to the treatment through different mechanisms. Hence, there is a pressing need to target ALK-dependent tumors by other therapeutic strategies, and possibly use them in combination with kinase inhibitors. In this review we will focus on the therapeutic potential of proapoptotic ALK-derived peptides based on the dependence receptor properties of ALK. We will also try to make a non-exhaustive list of several alternative treatments targeting ALK-dependent and independent signaling pathways.
Highlights
Anaplastic Lymphoma Kinase (ALK) was first discovered in 1994 as part of the nucleophosmin (NPM)-ALK fusion resulting from the highly recurrent (2;5)(p23;q35) translocation in anaplastic large cell lymphomas (ALCL) [1,2]
We investigated whether the P36 peptide could cooperate with a tyrosine kinase inhibitors (TKIs) to kill ALK-addicted two responsive cell lines, surface plasmon resonance followed by mass spectrometry analysis of tumor cells (Figure 2)
ALK is a receptor tyrosine kinase involved in many types of tumors
Summary
Anaplastic Lymphoma Kinase (ALK) was first discovered in 1994 as part of the nucleophosmin (NPM)-ALK fusion resulting from the highly recurrent (2;5)(p23;q35) translocation in anaplastic large cell lymphomas (ALCL) [1,2]. Palmer’s group showed that both FAM150A and FAM150B were able to bind and activate human wild type ALK, and constitutively active ALK mutants from neuroblastoma, resulting in a further enhanced activity or ‘superactivation’ [28] These secreted molecules have been named ALK and LTK ligands (ALKAL), as approved by HUGO Gene Nomenclature Committee. De Pontual et al reported two cases of germline gain-of-function mutations of ALK, associating severe defects of the central nervous system together with congenital neuroblastoma Their observations illustrate the role of activated ALK kinase in both tumor predisposition and normal development of the nervous system, and shed light on the pleiotropic role of ALK in humans [32]. Cancers normal development of the nervous system, and shed light on the pleiotropic role of ALK in humans [32]
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