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Review | Open Access

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

Tobias Boch1,2,3Jens Köhler1,2,3Melanie Janning1,2,3Sonja Loges1,2,3 ( )
DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim 68135, Germany
Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Department of Personalized Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim 68135, Germany
Show Author Information


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.



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Cancer Biology & Medicine
Pages 1543-1564
Cite this article:
Boch T, Köhler J, Janning M, et al. Targeting the EGF receptor family in non-small cell lung cancer—increased complexity and future perspectives. Cancer Biology & Medicine, 2022, 19(11): 1543-1564.








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Received: 02 September 2022
Accepted: 01 November 2022
Published: 05 December 2022
©2022 Cancer Biology & Medicine.

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