NSCLC and HER2: Between Lights and Shadows

Abstract

The therapeutic landscape of non-small-cell lung cancer (NSCLC) has dramatically changed in the last few years with the introduction of molecularly targeted agents, leading to unprecedented results in lung tumors with a paradigmatic shift from a "one size fits all" approach to an histologic and molecular-based approach. The discovery of epidermal growth factor receptor (EGFR) mutations in NSCLC in 2004 and the marked response to the EGFR tyrosine kinase inhibitor gefitinib, in a small subset of patients harboring these genetic abnormalities, stimulated the study of other kinase mutants involvement in NSCLC. The incredible story of ALK rearranged tumors, with the rapid Food and Drug Administration approval of Crizotinib after only 4 years from the discovery of EML4-ALK translocation in NSCLC, has profoundly influenced the concept of drug development in NSCLC, paving the way to a novel series of molecularly selected studies with specific inhibitors. The identification of these oncogenic drivers has dramatically changed the genetic landscape of NSCLC moving away from the old concept of a large indistinct histological entity to a combination of rare clinically relevant molecular subsets. Recently, a renewed interest has been emerging on the human epidermal growth factor-2 (HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time to be associated in NSCLC with different sensitivity to the EGFR tyrosine kinase inhibitors, to have a possible prognostic role and more recently HER2 amplification has been emerged as a possible mechanism in EGFR-mutated tumors of acquired resistance to the EGFR tyrosine kinase inhibitors. In addition, dysregulation of the HER2 pathway, in particular HER2 mutations (mostly, in-frame exon 20 insertions), may represent a possible novel therapeutic target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC patients with HER2 mutations, several targeted agents have been evaluated in HER2-mutated patients, generating a growing interest upon this oncogenic driver, leading to the design of molecularly selected trials with anti-HER2 compounds and the rediscover of hastily thrown out drugs, such as neratinib. The aim of this article is to provide an overview of the role of HER2 dysregulation in NSCLCs, trying to throw a light not only on the strengths but also the weaknesses of the studies conducted so far. It is a long way to the clinical implementation of these biomarkers and probably the increasing use of next generation sequencing techniques, the creation of large multi-institutional molecular testing platforms and the design of rationally based trials can get closer personalized medicine in NSCLC.

Lung Cancer Biomarkers

“…It encodes for a tyrosine kinase receptor member of the ERBB receptor family (47). HER2 lacks a specific ligand.…”

“…Nevertheless, it can be combined with other ERBB receptors to form a heterodimer (48). This allows for the activation of important signal transduction pathways, including the MAPK and PI3K pathways, involved in cell proliferation, differentiation, and migration (47). HER2 expression and/or amplification is found in many cancers including breast and gastric cancer (48).…”

“…HER2 expression and/or amplification is found in many cancers including breast and gastric cancer (48). Overexpression of HER2 has been reported in 7% to 34.9% of NSCLCs and has been associated with poor prognosis in patients with these tumors (47). Activating mutations of HER2 have been found in 1.6% to 4% of lung cancers (47, 49).…”

HER2 overexpression reverses the relative resistance of EGFR-mutant H1975 cell line to gefitinib

“…PI3K docking sites are absent on EGFR or HER2, however, docking sites for PI3K are highly prevalent on HER3 (29). It is noteworthy that HER2 is an orphan receptor for which no ligand has yet been identified, while the kinase activity of HER3 is defective (30). In this regard, EGFR and HER2 are not able to directly activate the PI3K/Akt pathway (20).…”

Molecular pathological predictive diagnostics in a patient with non‑small cell lung cancer treated with crizotinib therapy: A case report

“…Genetic aberrations of the EGFR signaling pathway in NSCLC are associated with a different sensitivity to EGFR TKI inhibitors in association with activating mutations on exons 19 and 21 (deletion and mutation L858R). It has been shown that HER2/neu amplification can result in acquired EGFR TKI resistance in EGFR-mutant tumors (7).…”