Studies of the Efficacy of Low-Dose Apatinib Monotherapy as Third-Line Treatment in Patients with Metastatic Colorectal Cancer and Apatinib’s Novel Anticancer Effect by Inhibiting Tumor-Derived Exosome Secretion

SIMPLE SUMMARY: We assessed the efficacy and safety of low-dose apatinib monotherapy as a third-line treatment in patients with metastatic colorectal cancer. The ORR and DCR were 4.0% (2/50) and 70% (35/50), and the median PFS and OS were 4.7 months and 10.1 months, which demonstrated comparable survival outcomes, significant improvements to the patient’s quality of life, and tolerable adverse reactions. We also disclosed a novel role of apatinib’s anticancer effect, i.e., inhibiting tumor-derived exosome release. Our results indicated that apatinib treatment inhibited exosome secretion through the regulation of MVB biogenesis, transport, and fusion by regulating LAMP2, RAB11, Snap23, and VAMP2. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib in CRC treatment. ABSTRACT: Antiangiogenic therapy is an important treatment strategy for metastatic colorectal cancer (mCRC). We carried out a clinical study of low-dose apatinib (250 mg) monotherapy as a third-line treatment in patients with mCRC and assessed its efficacy and safety. It demonstrated that low-dose apatinib had comparable survival outcomes, significantly improved the patient quality of life, and caused tolerable adverse reactions. To further investigate the underlying mechanism of the effects of apatinib in CRC besides angiogenesis, we performed RNA-seq, and our results suggested that apatinib may have other potential antitumor mechanisms in CRC through multiple pathways, including exosomes secretion. In RKO and HCT116 cells, apatinib significantly reduced exosomes secretion by targeting multivesicular body (MVB) transport. Further studies have indicated that apatinib not only promoted the degradation of MVBs via the regulation of LAMP2 but also interfered with MVB transport by inhibiting Rab11 expression. Moreover, apatinib inhibited MVB membrane fusion by reducing SNAP23 and VAMP2 expression. In vivo, apatinib inhibited orthotopic murine colon cancer growth and metastasis and reduced the serum exosomes amount. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib beyond angiogenesis inhibition.