Journal
MOLECULAR CANCER THERAPEUTICS
Volume 21, Issue 7, Pages 1060-1066Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0835
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HJM-561 is an orally bioavailable EGFR PROTAC that selectively degrades EGFR C797S-containing triple mutants, showing promising therapeutic option for overcoming drug resistance in NSCLC.
The EGFR C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non-small cell lung cancer (NSCLC). Currently there are no effective treatment options for patients with NSCLC harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/ T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild-type EGFR. Oral administration of HJM-561 shows robust antitumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC. [GRAPHICS] .
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