Cell cycle inhibitors for liver cancer treatment

Abstract

Cell cycle inhibitors have a long clinical history as cancer treatment. Cell cycle inhibitors are effective in suppressing cancer cells which undergo rapid cell division. We found that besides arresting cell cycle, the inhibitors combated cancer via a new mechanism – STING signaling pathway. We demonstrated that the common cell cycle drugs including Paclitaxel (microtubule stabilizer), Palbociclib (CDK4/6 inhibitor), AZD1152 and GSK1070916 (aurora kinase B inhibitors), and CFI-402257 (TTK inhibitor) have anti-cancer functions beyond arresting cell cycle. They consistently caused cytosolic DNA accumulation, which inadvertently triggered the cytosolic DNA sensor DDX41, and activated STING-TBK1-IRF3/7 pathway to secrete pro-inflammatory senescence-associated secretory phenotype (SASP). Interestingly, we found that DDX41 is a transcriptional target of hypoxia-inducible factor (HIF). Hypoxia induces expression of DDX41 through HIF-1, making hypoxic HCC cells more sensitive to the cell cycle inhibitors in STING activation and SASP production. The SASP altered the tumor microenvironment and triggered immune cells infiltration into tumor core for cancer clearance. We also showed that Paclitaxel, Palbociclib, and AZD1152 effectively perturbed HCC growth when used in combination with anti-PD-1 antibody. Our study revealed the novel immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested the potential of combined treatment with immunotherapy as a new therapeutic approach to eradicate HCC with promising result.

However, the greatest barricade that stops cell cycle inhibitors from being the most effective anticancer drugs is the resistance that gained by the cancer cells, possibly by escape or compensatory mechanism. Therefore, identifying the genes that contribute to drug resistance and understanding the mechanism behind are critical in sensitizing the resistant cells to the drug treatment again. By using genome-scale CRISPR-Cas9 knockout library, we identified CDC7 as TTK inhibitor-resistant gene. Inhibiting both TTK and CDC7 suppressed HCC tumor growth by accelerating DNA damage in cells and promoting genome instability. Our study suggested the potential of combined treatment of TTK inhibitor with CDC7 inhibitor to improve the efficacy of current liver cancer therapies and to block the tumor from acquiring resistance towards the anti-cancer drugs.