Molecular Pathways and Mechanisms of HER2 in Cancer Therapy

Abstract

The oncogene ERBB2 encoding the receptor tyrosine-protein kinase erbB-2 (HER2) is frequently overexpressed or amplified and occasionally mutated in a variety of human cancers. The early discovery of this oncogene, its established oncogenic relevance in diverse cancers, its substantial expression on the surface of cancer cells, and its druggable catalytic activity have made it one of the most pursued targets in the history of cancer drug development. Initiatives targeting HER2 provided the early stimulus for several transformational pharmaceutical technologies, including mAbs, tyrosine kinase inhibitors, antibody-drug conjugates, and others. The seismic impact of these efforts has been felt in treatment of many cancers, including breast, gastroesophageal, lung, colorectal, and others. This impact continues to broaden with increasing indications on the horizon and a plethora of novel agents in development. However, implementation of these therapeutic strategies has been complex. The clinical translation of every one of these classes of agents has been notable for underperformance or overperformance characteristics that have informed new lines of research providing deeper insights into the mechanistic complexities and unrealized opportunities provided by this molecular target. Despite all the successes to date, the preponderance of scientific evidence indicates that the full potential of HER2 as a target for cancer therapeutics is far greater than currently realized, and numerous lines of investigation are ongoing to deepen and broaden the scope of impact of HER2 as a signaling, homing, or immunologic target. In this review, we explore the existing data and evolving paradigms surrounding this remarkable target for cancer therapy.

Figure 1.. HER2 pathway and pharmacologic strategies

Schematic showing the structures and events occurring in HER2-amplified cancers and the site of binding of various HER2-targeted therapies. HER2 is shown in red and HER3 is shown in blue. HER3 is shown in the activated ligand-bound state as well as the inactive unbound state. HER2 only has one conformation always poised for dimerization. The shaded light blue enclosures highlight aspects of dimerization that are non-physiologic but occur in cancers propelled by the massive expression of HER2, reflecting the uncoupling of kinase domain dimerization and signaling from the ECDs and tolerance to antibody binding.

Figure 2.. Pan-cancer prevalence of HER2 alterations (mutations and amplifications)

Panel A shows ERBB2 alterations seen in 6% of 85,575 patients with diverse cancers as per the cancer genomic data aggregated through AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) effort (AACR Genie v11.0-public). Only tumor types with ≥ 10 cases and at least 1% prevalence were included. Panel B shows the oncoprint in the same cohort and highlights the type of mutations seen in these patients with limited overlap of mutations and amplifications.