Combining fruquintinib with TAS-102 as a promising strategy: antitumor activity in preclinical colorectal and gastric...

The combination of bevacizumab and TAS-102 has emerged as a treatment option for metastatic colorectal cancer (CRC). Bevacizumab is an anti-VEGF-A antibody, and TAS-102 is a cytotoxic nucleotide analog. Recently, fruquintinib, an oral, potent and highly selective inhibitor of all three vascular endothelial growth factor receptors (VEGFRs), has been approved for the treatment of chemorefractory CRC. The purpose of this study was to investigate the combined antitumor activity of fruquintinib and TAS-102 in CRC and gastric cancer (GC) models and to reveal possible mechanisms to explain the combined effects.

In vitro angiogenic and lymphangiogenic activities were studied by tube formation assays using HUVECs and HDLECs, respectively. Protein expression was measured by Western blot analysis. Intratumor drug concentrations were determined by liquid chromatography-tandem mass spectrometry analysis. Antitumor activity was studied in xenograft models.

Fruquintinib inhibited tube formation in both HUVECs and HDLECs. Trifluridine, an anti-neoplastic component of TAS-102, potentiated the inhibition of tube formation by fruquintinib in HUVECs but not in HDLECs. Suppression of VEGFR downstream signaling, together with induction of DNA damage response, was observed in HUVECs treated with the fruquintinib plus trifluridine combination. In an HT-29 CRC xenograft model, the intratumor levels of trifluridine and its active metabolites were higher following the fruquintinib plus TAS-102 combination treatment than following TAS-102 monotherapy. Antitumor studies demonstrated that the combination of fruquintinib and TAS-102 suppressed tumor growth more potently than individual agents in HT-29 and COLO-205 CRC xenograft models. The combined effect was comparable to that of bevacizumab plus TAS-102 in CRC models and was also observed in SC-2-JCK and MKN45 GC xenograft models. The addition of fruquintinib did not increase body weight loss caused by TAS-102 alone.

The combination of fruquintinib and TAS-102 improved antitumor activity in CRC and GC xenograft models, with in vitro evidence of enhanced anti-angiogenic activity of fruquintinib by trifluridine and ex vivo evidence of an increased amount of intratumor trifluridine with fruquintinib. Our data support testing the combination of fruquintinib and TAS-102 in clinical studies.