Abstract 543: SF2523, a dual PI3K-BRD4 inhibitor, enhances KRAS (G12C) or EGFR (exon 19/21) mutant targeted inhibitors in non-small-cell lung cancer (NSCLC)

Abstract KRAS and EGFR mutations are common oncogenic drivers in NSCLC. Osimertinib is a first line therapy for EGFR exon 19 and 21 mutant NSCLC. Sotorasib and Adagrasib are a second line therapy for KRAS G12C mutant NSCLC. Single agent inhibitors targeting mutant EGFR or KRAS develop drug resistance leading to relapsed/refractory NSCLC. SF2523 is a dual PI3K-bromodomain-containing protein 4 (BRD4) small molecule inhibitor being evaluated to mitigate KRAS or EGFR inhibitor induced drug resistance. Co-inhibition of PI3K/BRD4 blocks MYC expression, activation and enhances MYC degradation leading to inhibition of cancer growth and metastasis. We investigated SF2523 in EGFR mutant (HCC2935 and HCC827) and KRAS mutant (NCI H2030 & NCI H23) NSCLC cells lines with single agent or combination with Osimertinib or Sotorasib for anti-tumor activity, respectively. SF2523 IC50 in EGFR mutated NSCLC cells ranged from 90-230nM, while in KRAS mutated NSCLC cells ranged from 144-217nM versus Buparlisib plus JQ1 in the μM range. SF2523 plus Osimertinib decreased the IC50 to 1.2-1.4nM and SF2523 plus Sotorasib 1.6-13nM, respectively. In contrast, combinations of SF2523 plus Nindetinib (VEGFR inhibitor) or Rapamycin (mTOR inhibitor) were additive in potency with EGFR and KRAS mutant NSCLC cell lines. In KRAS mutant NSCLC treatment with SF2523 or Sotorasib increased PTEN mRNA expression and the combination therapy was additive. In EGFR mutant NSCLC treatment with SF2523 or Osimertinib or in combination decreased MYC, PIK3CA and AKT1, respectively. In a SCID H2030 KRAS G12C mouse xenograft model, SF2523 at a dose of 150 mg/kg was well tolerated without weight loss with tumor growth inhibition of >60% at 6 weeks. In conclusion, our results demonstrate SF2523 is active alone and is synergistic with Osimertinib or Sotorasib in inhibiting EGFR or KRAS mutant NSCLC cell lines and is active as a single agent in a KRAS G12C mutated H2030 CDX NSCLC mouse model. Citation Format: Baskaran Subramani, Patrick Joseph Conway, Kun Zhang, Guillermo A. Morales, Joseph R. Garlich, Daruka Mahadevan. SF2523, a dual PI3K-BRD4 inhibitor, enhances KRAS (G12C) or EGFR (exon 19/21) mutant targeted inhibitors in non-small-cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 543.