Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models

• Main Authors: Ilaria Marrocco, Donatella Romaniello, Itay Vaknin, Diana Drago‐Garcia, Roni Oren, Mary Luz Uribe, Nishanth Belugali Nataraj, Soma Ghosh, Raya Eilam, Tomer‐Meir Salame, Moshit Lindzen, Yosef Yarden
• Format: Article
• Language: English
• Published: Wiley 2021-04-01
• Series: EMBO Molecular Medicine
• Subjects: EGFR TKIs; first‐line therapy; mAbs; NSCLC; resistance
• Online Access: https://doi.org/10.15252/emmm.202013144
• ISSN: 1757-4676; 1757-4684

Abstract Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti‐cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first‐, second‐, and third‐generation drugs. To explore alternatives to such whack‐a‐mole strategies, we simulated in patient‐derived xenograft models the situation of patients receiving first‐line TKIs. Monotherapies comprising approved first‐line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug–drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance‐conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next‐generation TKIs.