Multitarget kinase inhibitor olverembatinib (HQP1351) is efficacious and synergizes with chemotherapy in preclinical models of endometrial carcinoma (EC)

Background: EC is the most common uterine cancer. Treatments for certain subtypes or advanced disease are limited. Olverembatinib is an investigational multikinase inhibitor targeting factors such as VEGFR1-3, FGFRs, SRC, PDGFRs, and RET. Drug sensitivity screening of 883 human cancer cell lines showed that EC is the second-most sensitive tumor type to olverembatinib, prompting us to explore antitumor effects of olverembatinib alone or combined with standard-of-care chemotherapy in preclinical EC models. Methods: PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) was used to screen olverembatinib activity in multiple cancer cell lines. Cell viability was assessed using CellTiter-Glo ® assays, and apoptosis was measured by flow cytometry. Western blotting was used to illustrate mechanisms of action. Subcutaneous MFE296 and AN3CA cell line-derived xenograft (CDX) models were established to evaluate antitumor effects in vivo . Results: Olverembatinib inhibited proliferation of 31 EC cell lines across different histological types, with IC 50 values ranging from subnanomolar to ~4 µM. Olverembatinib was significantly more potent (IC 50 up to 100-fold lower) than lenvatinib in cell growth inhibition in AN3CA, HEC-1B, RL95-2, and Ishikawa cells. Combinations of olverembatinib and paclitaxel or carboplatin were evaluated in AN3CA, HEC-1B, MFE296, and Ishikawa cells. All were resistant to carboplatin. Olverembatinib synergized with paclitaxel to inhibit cell proliferation and promote apoptosis. In the MFE296 CDX model, olverembatinib showed dose-dependent antitumor activity at day 29 with respective T/C values of 61.72% and 39.04% at 5 and 10 mg/kg. Combining paclitaxel (10 mg/kg) and carboplatin (50 mg/kg) with olverembatinib (10 mg/kg) significantly enhanced the latter's antitumor activity, with a T/C value of 9.08% and synergistic index of 1.37. Antitumor effects of olverembatinib and synergy with chemotherapy were recapitulated in AN3CA CDX models. No significant body weight loss was observed. Mechanistically, olverembatinib suppressed phosphorylation of oncogenic FGFR2, SRC, and PI3K-AKT (the most frequently altered pathway in EC) and downstream factors STAT3 and ERK. When olverembatinib was combined with chemotherapy, synergistic downregulation of the above pathways, cell cycle proteins (pRB, CDK4, and CDK6), and augmentation of apoptotic markers (cleaved caspase3 and PARP) and DNA damage marker (gammaH2AX) were observed, as well as modulation of epithelial-mesenchymal transition (tumor metastasis) markers. Conclusions: In a broad range of preclinical in vitro and in vivo EC models, olverembatinib is efficacious and synergizes with chemotherapy to promote antitumor effects. The findings support future clinical evaluation of olverembatinib and its combination with other approved treatment options in EC.