Epidermal growth factor receptor C797X mutant (EGFR C797X)

The Epidermal growth factor receptor (EGFR) C797X mutant represents a significant clinical challenge in the treatment of non-small cell lung cancer (NSCLC) (PubMed: 30545565). The C797 residue, located within the ATP-binding pocket of the EGFR kinase domain, is the critical site for covalent attachment of third-generation tyrosine kinase inhibitors (TKIs) like osimertinib (Nature Reviews Cancer, 2017). When this cysteine is mutated, most commonly to serine (C797S), the covalent bond can no longer form, rendering third-generation inhibitors ineffective and leading to disease progression (NCBI: NBK563047). This mutation often arises as an acquired resistance mechanism following treatment with osimertinib, frequently occurring alongside the T790M gatekeeper mutation (Journal of Thoracic Oncology, 2018). Current therapeutic strategies focus on developing fourth-generation TKIs, such as BLU-945 and BBT-176, that can inhibit EGFR even in the presence of the C797S mutation (ClinicalTrials.gov: NCT04862780). Understanding the specific configuration of these mutations, such as whether they occur in cis or trans, is vital for determining the efficacy of combination therapies involving earlier-generation inhibitors (Cancer Discovery, 2017). These mutants maintain the oncogenic signaling pathways that drive tumor growth, necessitating the development of inhibitors with high selectivity over wild-type EGFR to minimize toxicity (PubMed: 33233456).

Other names

EGFR C797SErbB-1 C797XHER1 C797XEpidermal growth factor receptor C797S mutation

Tyrosine kinase inhibition