Targeting ALK in Cancer: Therapeutic Potential of Proapoptotic Peptides

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.

Keywords: ALK; anaplastic large cell lymphoma; anaplastic lymphoma kinase; dependence receptor; neuroblastoma; non-small-cell lung cancer; proapoptotic peptides; targeted therapy; tyrosine kinase; tyrosine kinase inhibitor.

Figure 1

Model for Anaplastic Lymphoma Kinase (ALK) positive and negative signaling. ALK receptor activation requires homodimerization and transphosphorylation of its tyrosine kinase domain. (A) ALK activation can be achieved in the presence of a ligand (left), or constitutively (right) when ALK is either amplified, mutated, involved in a fusion such as NPM-ALK, or a product of ALK alternative initiation of transcription (ALK^ATI). Note that the subcellular localization of all these ALK isoforms is different: the wild type or mutant full length receptor is localized at the cell membrane, whereas NPM-ALK and ALK^ATI are intracellular, as they lack the extracellular and transmembrane domains of ALK. Both NPM-ALK and ALK^ATI also localize to the nucleus (and nucleolus for NPM-ALK), however, only ALK^ATI homodimerizes and is activated in this compartment, and therefore is represented on this schema. Its function in the nucleus needs to be clarified, although it is reported to induce chromatin modifications. Signaling triggered by activated ALK includes the STAT3, ERK, PLCγ, and PI3K/Akt pathways leading to cell proliferation, differentiation, and survival. (B) In the absence of ligand, the ALK receptor promotes apoptosis via caspase 3 activation through mitochondrial release of cytochrome C. In this state, the kinase is inactive and the receptor likely monomeric. Inactive ALK (non-ligated or kinase inactive) is cleaved by caspase 3, thus exposing the ADD intracellular domain (upstream of the cleavage site) and amplifying apoptosis in a positive feedback loop. TM: transmembrane; TK: tyrosine kinase; P: phosphorylation on tyrosine residues; ADD: addiction/dependence domain; Mito: mitochondria; Cyt C: cytochrome C.

Figure 2

ALK targeting at two fronts. Targeting ALK tyrosine kinase domain with a specific inhibitor can decrease tumor cell proliferation and induce apoptosis. On the other hand, ALK-derived peptides mimicking the ADD domain of ALK were found to be proapoptotic. A combination treatment can bring additive or synergistic efficiency to kill ALK-dependent tumors.