Abstract
Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and kill tumor cells with naturally inherited or engineered properties. Considering the limitations of OVs monotherapy, combination therapy has been widely explored. MEK inhibitor (MEKi) Trametinib is an FDA-approved kinase inhibitor indicated for the treatment of tumors with BRAF V600E or V600K mutations. In this study, the oncolytic activity in vitro and anti-tumor therapeutic efficacy in vivo when combined with oHSV and MEKi Trametinib were investigated. We found: (1) Treatment with MEKi Trametinib augmented oHSV oncolytic activity in BRAF V600E-mutated tumor cells. (2) Combination treatment with oHSV and MEKi Trametinib enhanced virus replication mediated by down-regulation of STAT1 and PKR expression or phosphorylation in BRAF V600E-mutated tumor cells as well as BRAF wt/KRAS-mutated tumor cells. (3) A remarkably synergistic therapeutic efficacy was shown in vivo for BRAF wt/KRAS-mutated tumor models, when a combination of oHSV including PD-1 blockade and MEK inhibition. Collectively, these data provide some new insights for clinical development of combination therapy with oncolytic virus, MEK inhibition, and checkpoint blockade for BRAF or KRAS-mutated tumors.
Highlights
Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and destroy tumor cells with naturally inherited or engineered properties [1]
(2) Combination treatment with Oncolytic herpes virus (oHSV) and MEK inhibitor (MEKi) Trametinib enhanced virus replication mediated by down-regulation of STAT1 and PKR expression or phosphorylation in BRAF V600E-mutated tumor cells as well as BRAF wt/KRAS-mutated tumor cells
(3) A remarkably synergistic therapeutic efficacy was shown in vivo for BRAF wt/KRAS-mutated tumor models, when a combination of oHSV including PD-1 blockade and MEK inhibition
Summary
Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and destroy tumor cells with naturally inherited or engineered properties [1]. The combination of OVs with other immunotherapies, especially immune checkpoint blockade (ICB) can exert synergistic effect to increase therapeutic effects against tumors [1,3]. The pharmacoviral approaches combining OVs with molecular therapeutics targeting kinases commonly linked to cancer development showed remarkably synergistic responses during tumor treatment [4]. The mitogen-activated protein kinase (MAPK) cascade (RAS/RAF/MEK/ERK), which is one of the most dysregulated pathways in human cancers, regulates multiple critical cellular functions including proliferation, growth, survival and motility [5,6]. The mutations involving the GTP-ase RAS protein family and its downstream BRAF lead to loss of cell cycle regulation at key checkpoints, which are the main driver mutations for several tumor types, e.g., colorectal carcinogenesis [8]
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