The Novel IGF-1R Inhibitor PB-020 Acts Synergistically with Anti-PD-1 and Mebendazole against Colorectal Cancer

SIMPLE SUMMARY: Colorectal cancer (CRC) is generally diagnosed at an advanced stage, when chemo- and targeted therapies can only achieve a limited increase in overall survival for these patients. The activation of insulin/IGF-dependent pathways has been established as a key step that contributes to several mechanisms of CRC resistance to conventional and targeted therapeutic drugs. In this study, we tested the combinatory effect of the novel IGF-1R inhibitor PB-020 and MBZ or anti-PD-1 against CRC, respectively. The PB-020/MBZ combination significantly reduced the pAKT1-S473 level, dampened the viability of CRC cells and blocked CRC progression in a xenograft model. More importantly, the PB-020/anti-PD-1 combination synergistically blocked CRC propagation in the MC38 murine colon carcinoma model. RNA-seq analysis indicated that PB-020 and the anti-PD-1 antibody synergistically suppressed the transcription of the PI3K/AKT pathway genes. These findings establish a preclinical proof-of-concept for tackling CRC using a combination of PB-020 and clinically approved anticancer drugs. ABSTRACT: CRC is one of the leading causes of cancer mortality worldwide. Chemotherapy is widely used for the treatment of CRC, but its efficacy remains unsatisfactory, mainly due to drug resistance. Therefore, it is urgent to develop new strategies to overcome drug resistance. Combination therapy that aims to achieve additive or synergistic therapeutic effects is an effective approach to tackle the development of drug resistance. Given its established roles in tumor development, progression and metastasis, IGF-1R is a promising drug target for combination therapy against CRC. In this study, we revealed that the novel IGF-1R inhibitor PB-020 can act synergistically with mebendazole (MBZ) to reduce the viability of CRC cells and block xenograft CRC progression. Moreover, the PB-020/anti-PD-1 combination synergistically blocked CRC propagation in the MC38 murine colon carcinoma model. Both combination therapies potently suppressed the PI3K/AKT signaling pathway genes in CRC that may be associated with the development of drug resistance. Our findings establish a preclinical proof-of-concept for combating CRC using combined multi-target treatment with PB-020 and clinical anticancer drugs, which may provide useful clues for clinical trials to evaluate the efficacy and safety of these drug combinations in CRC patients.