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.

Emerging Roles of ALK in Immunity and Insights for Immunotherapy

“…Interestingly, both ALK and LTK share common endogenous ligands, Augmentor α (or FAM150B, ALKAL2) and Augmentor β (or FAM105A, ALKAL1, with relatively higher affinity for LTK) [3,4]. The high sequence homology between ALK and LTK, and their shared ligands support the notion that ALK may have resulted from gene duplication [5].…”

Upregulation of the Coatomer Protein Complex Subunit beta 2 (COPB2) Gene Targets microRNA-335-3p in NCI-H1975 Lung Adenocarcinoma Cells to Promote Cell Proliferation and Migration

“…Surgical resection is the main first-line treatment for adenocarcinoma of the lung. In advanced NSCLC, patients are also treated with chemotherapy and targeted therapy, including epidermal growth factor receptor (EGFR) inhibitors [4], anaplastic lymphoma kinase (ALK) inhibitors [5], and immunotherapy, including immune checkpoint inhibitors [6,7]. Despite these recent clinical advances, the treatment of adenocarcinoma of the lung remains challenging due to tumor invasion, early metastasis, and drug resistance of tumor cells [8].…”

1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42), a novel ALK inhibitor, induces apoptosis and protective autophagy in H2228 cells

“…Therefore, the EML4-ALK oncogene has become a new target for individualized treatment of NSCLC. [7] Crizotinib (PF-02341066) was the first FDA-approved drug for the treatment of ALK-positive NSCLC. Crizotinib is a multitarget tyrosine kinase inhibitor of ALK, ROS1 and other genes.…”