Abstract
T790M mutation is the most common mechanism for resistance to first- and second-generation tyrosine kinase inhibitors (TKI) for epidermal growth factor receptor (EGFR). Several third-generation EGFR mutant selective TKIs are being explored to conquer this resistance. AZD9291 (osimertinib, tagrisso) has been approved for treatment of the metastatic EGFR T790M mutation-positive non-small cell lung cancer. Resistance to AZD9291 has been described. C797S mutation was reported to be a major mechanism for resistance to T790M-targeting EGFR inhibitors. This review summarizes the latest development in identifying the C797S mutation and EAI045, the novel selective inhibitor overcoming the C797S mutant.
Highlights
T790M mutation is the most common mechanism of resistance to the first- and second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) [1]
Clinical trials are being done for several T790M-targeting third-generation EGFR-TKIs [2, 3]
A better understanding of the mechanisms of resistance to these thirdgeneration EGFR inhibitors is critical for developing new strategies to treat these patients [11]
Summary
T790M mutation is the most common mechanism of resistance to the first- and second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) [1]. She was enrolled in the phase 1 AURA study of AZD9291 (NCT01802632) and received AZD9291 for 9 months prior to disease progression Tumor biopsy at this juncture showed the EGFR C797S mutation, in addition to the del 19 and T790M. In the presence of del 19 or L858R and T790M, C797S mutation leads to resistance to all current EGFR inhibitors (gefitinib, afatinib, WZ4002, CO-1686, and AZD9291), but L858R/T790M/C797S mutant remains partially sensitive to cetuximab It remains to be determined whether cetuximab or cetuximab-based combinations are effective clinically in NSCLC patients that develop the L858R/T790M/C797S mutant clone. Re-biopsy of the AZD9291 resistant tumor identified an EGFR activating mutation and CMET amplification without T790M or C797S mutation These two cases indicated that in refractory NSCLC without T790M or C797S mutations, additional gene mutations or amplifications of tyrosine kinases other than EGFR can be the mechanisms of resistance. EAI045 represents a novel selective inhibitor that can overcome T790M and C797S resistance mutations [21]
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