Abstract 4476: BI-732, a novel fourth-generation EGFR-TKI, demonstrates promising activities against the C797S-mediated EGFR-TKI resistance
Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard modality of the 1st-line treatments for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). The FDA approved osimertinib, a third-generation EGFR-TKI, is highly selective for EGFR-activat...
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Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.4476-4476 |
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Zusammenfassung: | Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard modality of the 1st-line treatments for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). The FDA approved osimertinib, a third-generation EGFR-TKI, is highly selective for EGFR-activating mutations (exon 19 deletion [del19] or L858R point mutation in exon 21 [L858R]) as well as EGFR-T790M mutation. Nevertheless, resistance inevitably emerges and leads to disease progression. Acquired EGFR-C797S mutation is the most common on-target resistance mechanism to osimertinib in first- and second-line settings, and there are currently no approved targeted therapies. We aimed to evaluate the efficacy of BI-732, a fourth-generation EGFR-TKI developed to overcome the C797S mutation. Materials and Methods: We constructed several types of Ba/F3 cells expressing EGFR mutations containing the C797S mutation as follows: EGFRdel19/C797S, EGFRL858R/C797S, EGFRdel19/T790M/C797S, and EGFRL858R/T790M/C797S. We also constructed PC9 cells harboring EGFRdel19/C797S (named PC9-DC cells) using the CRISPR/Cas9 system. Furthermore, we generated two patient-derived cells, YU-1097 with EGFRdel19/T790M/C797S and YU-1182 with EGFRL858R/C797S. The in vitro efficacy of BI-732 was tested in several cell lines harboring the EGFR-C797S mutation mentioned above. We further evaluated in vivo antitumor activity of BI-732 in subcutaneous YU-1097 xenograft model and intracranial YU-1097-tumor model.Results: BI-732 effectively inhibited the viability of Ba/F3 cells expressing EGFRdel19/C797S (IC50, 6.8 nM), EGFRL858R/C797S (IC50, 213.4 nM), EGFRdel19/T790M/C797S (IC50, 3.8nM), and EGFRL858R/T790M/C797S (IC50, 15.2 nM), concomitant with marked reduction in EGFR and downstream signal phosphorylation. Moreover, BI-732 exhibited comparable nanomolar in vitro activity to osimertinib on EGFR activating mutation while sparing wild-type EGFR activity. We further confirmed the superior antiproliferative efficacy of BI-732 in PC9-DC (IC50, 24.9 nM), YU-1182 (IC50, 73 nM) and YU-1097 cells (IC50, 2.9 nM). Oral administration of BI-732 at a concentration of 25 mg/kg as a single agent resulted in significant tumor regression with 183.2% tumor growth inhibition (TGI) in the subcutaneous YU-1097 xenograft model. In a combination treatment strategy with osimertinib, BI-732 showed enhanced antitumor activity at much lower concentrations than monotherapy. BI-732 also demonstrated the ability to penetrat |
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ISSN: | 1538-7445 1538-7445 |
DOI: | 10.1158/1538-7445.AM2023-4476 |