Non-Canonical Thinking for Targeting ALK-Fusion Onco-Proteins in Lung Cancer.

Wei Wu,Trever Bivona,Franziska Haderk

doi:10.3390/cancers9120164

Abstract

Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified in lung cancer at 3–7% frequency, thus representing an important subset of genetic lesions that drive oncogenesis in this disease. Despite the availability of multiple FDA-approved small molecule inhibitors targeting ALK fusion proteins, drug resistance to ALK kinase inhibitors is a common problem in clinic. Thus, there is an unmet need to deepen the current understanding of genomic characteristics of ALK rearrangements and to develop novel therapeutic strategies that can overcome ALK inhibitor resistance. In this review, we present the genomic landscape of ALK fusions in the context of co-occurring mutations with other cancer-related genes, pointing to the central role of genetic epistasis (gene-gene interactions) in ALK-driven advanced-stage lung cancer. We discuss the possibility of targeting druggable domains within ALK fusion partners in addition to available strategies inhibiting the ALK kinase domain directly. Finally, we examine the potential of targeting ALK fusion-specific neoantigens in combination with other treatments, a strategy that could open a new avenue for the improved treatment of ALK positive lung cancer patients.

Highlights

The human Anaplastic lymphoma kinase (ALK) gene is located on chromosome 2p23.2 and encodes an enzymatic protein, known as ALK tyrosine kinase receptor or CD246
This is evident in recent studies [29], which demonstrated that specific lysine residues (e.g., 1451, 1455 and 1610) in echinoderm microtubule-associated protein-like 4 (EML4)-ALK proteins were methylated by a lysine methyltransferase, SET and MYND
Oligomerization and activation of ALK due to distinct intracellular localization at microtubules (EML4, KIF5B, TRK-fused gene (TFG), Dynactin subunit 1 (DCTN1), protein phosphatase non-receptor type 3 (PTPN3), and Kinesin light chain 1 (KLC1)) or cellular membranes (SQSTM1, TPR, Cysteine-rich motor neuron 1 protein (CRIM1), STRN, Huntingtin-interacting protein 1 (HIP1), and Clathrin heavy chain 1 (CLTC)) is likely to be of central relevance for ALK-mediated oncogenesis and presents a new therapeutic target for the treatment of ALK fusion driven cancers

Summary

Introduction

The human Anaplastic lymphoma kinase (ALK) gene is located on chromosome 2p23.2 and encodes an enzymatic protein, known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246). The expression levels of ALK mRNA and protein are diminished after birth and maintain relatively low levels in most tissues (Figure 1B, adopted from [2]), except showing high expression in the brain suggesting an important role in brain development [3]. This finding is supported by the behavioral phenotype apparent in ALK gene knockout mice [4]. ALK receptors are dimerized, resulting in kinase domain phosphorylation and the activation of multiple downstream signaling pathways such as JAK/STAT3, PI3K/AKT, RAS/MAPK and PLC-γ pathways (Figure 1C). NSCLC, propose non-canonical ideas to manipulate the partner proteins in ALK fusions, and propose the design of novel immune-epitopes for potential ALK fusion targeted immunotherapy

Genomic Characteristics of ALK Fusion-Driven NSCLC

ALK Fusion Partner Proteins as Potential Therapeutic Targets

Findings

Conclusions and Future Perspectives