A Structural Insight Into Two Important ErbB Receptors (EGFR and HER2) and Their Relevance to Non‐Small Cell Lung Cancer

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Abstract
The epidermal growth factor receptor (EGFR) family, comprising receptor tyrosine kinases (RTK) such as EGFR and HER2, plays a critical role in various signaling pathways related to cell proliferation, differentiation, and growth. EGFR overactivation due to aberrant signaling can lead to various cancers, including non‐small cell lung cancer (NSCLC). To develop treatment for EGFR‐related NSCLC, several tyrosine kinase inhibitors (TKIs) were designed: gefitinib, erlotinib, as first‐generation; neratinib, dacomitinib as second‐generation; osimertinib, lazertinib as third‐generation, as examples. However, due to the acquired resistance by the mutations such as EGFRT790M and EGFRC797S together with the exon 20 insertion mutations, these drugs do not provide promising results for NSCLC patients. The development of fourth‐generation inhibitors like EAI045 and further innovative drugs to overcome this resistance problem is a must to cure EGFR‐related NSCLC. Among these, pyrazoline‐thiazole scaffolds are found effective as EGFR‐HER2 inhibitors against NSCLC, making them promising drug candidates. Although structures obtained so far for the EGFR family provide meaningful insights into the mechanisms, the quality and the quantity of the EGFR family structures are insufficient to elucidate the complete structures and functions to overcome NSCLC. This review evaluates the structures of EGFR‐HER2 and investigates their relation to NSCLC.

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