Effect of carotuximab (ENV105)-mediated CD105 blockade on osimertinib sensitivity in EGFR-mutant non-small cell lung cancer persister cells.

e20009 Background: Osimertinib resistance in patients with EGFR-driven non-small cell lung cancer (NSCLC) contributes to mortality. Targeting bypass alterations have had limited efficacy. Here, we explored the role of CD105 (endoglin) expression, a co-receptor for bone morphogenetic protein (BMP) signaling as a factor of osimertinib treatment. Methods: Sixty-six NSCLC tumors, 44 of which had EGFR mutations were subjected to imaging mass cytometry to identify CD105 expression status as a predictor of clinical outcomes. To study the effects of EGFR and CD105 disruption two osimertinib-resistant EGFR-mutant cell lines were developed for subsequent characterization by single cell RNA sequencing. The promoter chromatin status and glycolytic state of the lines were evaluated by ATAC sequencing and Single Cell ENergetIc metabolism by profiling Translation inHibition analysis (SCENITH), respectively. Results: There was an inverse correlation between the expression CD105 and overall survival in treatment-naïve patients ( P = 0.0071). Modeling osimertinib resistance highlighted the emergence of a persister cell population expressing tumor dormancy features. Further, the persister cells were found to have elevated CD105 levels with responsivity to the neutralizing antibody, carotuximab (ENV105), in restoring epigenetic and metabolic reprogramming to support osimertinib sensitivity. The carotuximab mechanism of action was through the re-engagement of EGFR signaling by potentiating physical CD105/EGFR interaction. Combination of osimertinib and carotuximab significantly reduced tumor growth in two independent NSCLC mouse models ( P = 0.0056 and P = 0.0008), where either single agent had little benefit. Conclusions: CD105 targeting provides a novel mutation-independent strategy to overcome resistance in EGFR-mutant NSCLC. Based on the efficacy of carotuximab capacity to limit tumor dormancy and restored osimertinib sensitivity, a Phase 1 trial (NCT05401110) investigating the combination therapy is currently accruing subjects.