Targeting the EGF receptor family in non-small cell lung cancer-increased complexity and future perspectives

Abstract

Lung cancer remains the leading cause of cancer-associated mortality worldwide, but with the emergence of oncogene targeted therapies, treatment options have tremendously improved. Owing to their biological relevance, members of the ERBB receptor family, including the EGF receptor (EGFR), HER2, HER3 and HER4, are among the best studied oncogenic drivers. Activating EGFR mutations are frequently observed in non-small cell lung cancer (NSCLC), and small molecule tyrosine kinase inhibitors (TKIs) are the established first line treatment option for patients whose tumors bear "typical/classical" EGFR mutations (exon 19 deletions, L858R point mutations). Additionally, new TKIs are rapidly evolving with better efficacy to overcome primary and secondary treatment resistance (e.g., that due to T790M or C797S resistance mutations). Some atypical EGFR mutations, such as the most frequent exon 20 insertions, exhibit relative resistance to earlier generation TKIs through steric hindrance. In this subgroup, newer TKIs, such as mobocertinib and the bi-specific antibody amivantamab have recently been approved, whereas less frequent atypical EGFR mutations remain understudied. In contrast to EGFR, HER2 has long remained a challenging target, but better structural understanding has led to the development of newer generations of TKIs. The recent FDA approval of the antibody-drug conjugate trastuzumab-deruxtecan for pretreated patients with HER2 mutant NSCLC has been an important therapeutic breakthrough. HER3 and HER4 also exert oncogenic potential, and targeted treatment approaches are being developed, particularly for HER3. Overall, strategies to inhibit the oncogenic function of ERBB receptors in NSCLC are currently evolving at an unprecedented pace; therefore, this review summarizes current treatment standards and discusses the outlook for future developments.

Keywords: EGFR; HER2; HER3; HER4; NSCLC; Oncology.

Figure 1

ERBB receptor-dependent signaling. The binding of growth factors to ERBB/HER family members induces the phosphorylation of tyrosine kinases and subsequent activation of downstream signaling pathways such as Ras-RAF-MEK-ERK (extracellular signal-regulated kinases); PI3K (phosphoinositide 3-kinase)–PDK1 (3-phosphoinositide-dependent protein kinase 1), AKT (protein kinase B)–mTOR (mammalian target of rapamycin); PLC γ (phospholipase C γ), PKC (protein kinase C) and JAK (Janus kinase)-STAT (signal transducers and activators of transcription). EGF (epidermal growth factor), TNFα (tumor necrosis factor α), EPF (extracellular protein factor), EPR (epiregulin), BTC (betacellulin), HB-EGF (heparin-binding epidermal growth factor), Nrg1–4 (neuregulin 1–4). Created with BioRender.com.

Figure 2

EGFR protein domains and most frequent mutations. The extracellular domain of EGFR is composed of 2 extracellular ligand-binding domains (I and III) as well as 2 cysteine-rich domains (II and IV) that support dimer formation. It is linked via a single-α-helix transmembrane domain (TM) to the intracellular domain, which consists of a tyrosine kinase domain (TK) and a carboxy-terminal regulatory domain (Reg.). Activating gene mutations affecting the tyrosine kinase domain occur in exons 18–21. Exon 19 deletions and L858R point mutations are so-called “classical mutations” and occur in 70%–90% of cases. Atypical mutations occur primarily in exon 20. Beyond the common T790M mutation, exon20 insertion mutations are of particular relevance. Frequencies of different exon20 insertion mutations are displayed in brackets. Created with BioRender.com.

Figure 3

Diagnostic workflow after disease progression and most common resistance mechanisms to EGFR tyrosine kinase inhibitors. In patients who experience progression after treatment with first or second generation EGFR TKIs, a liquid biopsy with next-generation sequencing should be performed to determine the most common resistance mutation, T790M. If T790M negativity is found, liquid biopsy should be repeated, and additional tissue biopsies should be obtained if clinically feasible. In patients progressing after initial treatment with third generation TKIs (such as osimertinib), early tissue biopsy and additional liquid biopsy should be performed. The most common resistance mechanisms, such as MET amplification (METamp) or small-cell lung cancer (SCLC) transformation, are listed. MET (mesenchymal-epithelial transition), HER2 (human epidermal growth factor receptor2), BRAF (v-raf murine sarcoma viral oncogene homolog B1), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α), EMT (epithelial-mesenchymal transition), KRAS (Kirsten rat sarcoma virus), CCND1 (cyclin D1), CDK 4/6 (cyclin-dependent kinase 4/6), ALK (anaplastic lymphoma kinase), RET (rearranged during transfection). Created with BioRender.com.

Figure 4

Different modes of HER2 activation and treatment options in NSCLC. In NSCLC, HER2 alterations include HER2 overexpression, HER2 gene amplification and HER2 mutations. Current treatment options consist of the monoclonal antibodies trastuzumab and pertuzumab, the antibody-drug conjugates (ADC) trastuzumab-emtansine (T-DM) and trastuzumab-deruxtecan (TDXd), as well as tyrosine kinase inhibitors targeting HER2 mutations. Approved drugs are depicted in green. Created with BioRender.com.