ALK alterations and inhibition in lung cancer

Abstract

The advent of precision medicine in non-small cell lung cancer has remarkably altered the direction of research and improved clinical outcomes. The identification of molecular subsets with differential response to targeted therapies began with the identification of epidermal growth factor receptor mutated tumors in subsets of non-small cell lung cancer (NSCLC). Emboldened by unprecedented response rates to kinase inhibitors seen in that subset, the oncologic community searched for other molecular subsets featuring oncogene addiction. An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene. In an astoundingly brief period following the recognition of ALK-positive NSCLC, details of the biology, clinicopathologic features, development of targeted inhibitors, mechanisms of therapeutic resistance, and new generations of treatment were elucidated. This review summarizes the current understanding of the pathologic features, diagnostic approach, treatment options, resistance mechanisms, and future research areas for ALK-positive NSCLC.

The value of cell block based on fine needle aspiration for lung cancer diagnosis

“…Patients with ALK rearrangement comprise 2-5% of all NSCLC cases (21). In our study, we tested all NSCLC cases for ALK rearrangement using IHC.…”

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

“…Anaplastic lymphoma kinase (ALK), known as ALK tyrosine kinase receptor or cluster of differentiation 246 (CD246), has been identified as one of the major oncogenes in tumor pathogenesis [8, 11, 12, 16, 21, 26, 51]. In NB, high expression levels of ALK closely correlates with poor outcomes, especially in high-risk NB [22, 42, 49].…”

“…In addition, ALK -activating point mutations have been identified in approximately 8% of investigated NB tumors [1]. In prior studies, inhibition of ALK led to a significant decrease in cell proliferation in ALK -positive cancers, including non-small cell lung cancer (NSCLC) [26, 27, 29], anaplastic large cell lymphoma (ALCL) [6, 34] and NB [15, 44, 50, 52]. ALK-targeted chemotherapies have been shown to downregulate PI3K/Akt signaling, leading to cell apoptosis and tumor regression [4, 15, 51, 52].…”

Oncogene addiction and tumor mutational burden in non‐small‐cell lung cancer: Clinical significance and limitations

“…ALK‐ rearrangements have been discovered recently as an important driver mutation in NSCLC, and especially in advanced‐stage NSCLC, ALK‐ mutation status has a major impact on how patients are treated . ALK rearrangement is found in 3%–7% of patients suffering from stage IIIB or stage IV NSCLC, according to previous data . Adenocarcinomas harbor ALK mutations more frequently than squamous cell carcinomas.…”

“…Adenocarcinomas harbor ALK mutations more frequently than squamous cell carcinomas. Interestingly, if only non‐smoker patients are considered, the prevalence of ALK rearrangement is much higher, ranging from 17% to 20%, depending on the case series …”