Abstract
<div>Abstract<p>Purpose: Resistance to third-generation epidermal growth factor receptor (EGFR) inhibitors including osimertinib arises in part from the C797S mutation in <i>EGFR</i>. Currently, no targeted treatment option is available for these patients. We have developed a new EGFR tyrosine kinase inhibitor (TKI), BBT-176, targeting C797S mutation. Patients and Methods: Recombinant EGFR proteins and Ba/F3 cell lines, patient-derived cells and patient-derived xenografts expressing mutant <i>EGFRs</i> were used to test the inhibitory potency and the efficacy of BBT-176 both <i>in vitro</i> and <i>in vivo</i>. Patient cases are derived from an ongoing phase 1 clinical trial (NCT04820023). Results: The half maximal inhibitory concentration (IC<sub>50</sub>) of BBT-176 against EGFR 19Del/C797S, EGFR 19Del/T790M/C797S, and EGFR L858R/C797S protein were measured at 4.36, 1.79 and 5.35 nM, respectively (vs. 304.39, 124.82, and 573.72 nM, for osimertinib). IC<sub>50 </sub>values of BBT‑176 against Ba/F3 cells expressing <i>EGFR</i> 19Del/C797S, <i>EGFR</i> 19Del/T790M/C797S, <i>EGFR</i> L858R/C797S, and <i>EGFR</i> L858R/T790M/C797S were 42, 49, 183 and 202 nM, respectively (vs 869, 1134, 2799, and 2685 nM for osimertinib). N-Ethyl-N-nitrosourea (ENU) mutagenesis suggested that BBT-176 treatment does not introduce any secondary mutations in the <i>EGFR</i> gene but increases EGFR expression levels. Combined with the EGFR antibody cetuximab, BBT‑176 effectively suppressed the growth of BBT-176-resistant clones. BBT‑176 strongly inhibited the tumor growth, and in some conditions induced tumor regression in mouse models. In the clinical trial, two patients from harboring <i>EGFR</i> 19Del/T790M/C797S in blood showed tumor shrinkage and radiological improvements. Conclusions: BBT-176 is a fourth-generation EGFR inhibitor showing promising preclinical activity against NSCLC resistant to current EGFR TKIs.</p></div>
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