Abstract P256: Pan-ErbB inhibition enhances activity of KRASG12C inhibitors in preclinical models of KRASG12C mutant cancers

• Published in: Molecular cancer therapeutics 2021-12, Vol.20 (12_Supplement), p.P256-P256
• Main Authors: Robichaux, Jacqulyne P., Galan-Cobo, Ana, Powell, Ried T., Gale, Kelly A., He, Jun, Zhang, Fahao, Nilsson, Monique B., Zhang, Xiang, Sobieski, Mary M., Nguyen, Nghi, Clifford, Stephan C., Heymach, John V.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-21-P256

Sotorasib (AMG 510) is the first KRAS inhibitor to be FDA-approved for the treatment of KRASG12C mutant lung adenocarcinomas which comprise ~42% of KRAS mutations in lung adenocarcinomas. Preclinical studies have shown that within hours of KRASG12C inhibition, synthesis of new KRASG12C protein and increased KRAS signaling was observed, leading to enhanced tumor cell growth and survival. This appeared to be due, at least in part, to a feeback loop leading to activation of EGFR signaling but the role of other ErbB family members including ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4) has not been fully evaluated. We hypothesize that short-term adaptation to KRAS inhibition is driven by multiple ErbB family members, and that the combination of pan-ErbB inhibitors with KRASG12C inhibitors could enhance KRASG12C inhibitor activity and prolong survival in preclinical models harboring KRASG12C mutations to a greater extent than more specific EGFR inhibitors. To investigate the role of different ErbB family members in this feedback signaling, we evaluated the impact of an EGFR specific inhibitor, erlotinib, an EGFR/HER2 inhibitor, afatinib, or pan-ErbB inhibitor (EGFR/HER2/3/4), poziotinib on anti-tumor activity of KRASG12C inhibitors in KRASG12C mutant NSCLC cell lines. We initially tested the different inhibitors in combination with sotorasib and adagrasib (MRTX849) and calculated the BLISS index (BI) for each drug pair matrix, using SynergyFinder. We found that when combined with either sotorasib or adagrasib, poziotinib had a synergistic effect (BI>10) in H23 (BI: 17, p=0.01), HCC44 (BI: 11, p=0.04), and H1792 (BI: 13, p=0.01) and an additive effect (BI= -10–10) in H2122 (BI: 2.8). Afatinib and erlotinib were additive in H23 (BI: 9.2 & 9.4), HCC44 (BI:8.8 & 7.9), H2122 (BI: -4.5 & -3.3) and H1792 (BI: 6.6 & 3.3). Poziotinib yielded a higher BI across all four cell lines compared to afatinib (p