Tumor-infiltrating polymorphonuclear neutrophils (PMNs) play an important role in the pathogenesis of colorectal cancer (CRC) by negatively altering DNA repair in tumor cells, but distinct CRC tumor phenotypes can be effectively treated with olaparib, a study in Gastroenterology suggests.

A team of investigators from the United States and Europe performed expression analyses on freshly frozen, resected human CRC tissue biopsies. Histological analyses of gastrointestinal (GI) features were performed using colon cancer tissue arrays. All experimental procedures were performed on CRC mice models. The researchers examined changes in the double strand break (DSB) repair landscape and looked to identify specific CRC responses both with and without tumor-infiltration by PMNs.

There was a mutual correlation between the formation of micronuclei and lagging chromosomes across 70 CRC tissue biopsies. Both GI markers were also highly associated with the presence of intratumoral PMNs. Homologous recombination (HR) deficiency was promoted by PMNs in low-grade CRC via miR-155-dependent RAD51downregulation. The investigators noted that this subsequently attenuated tumor growth.


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Accumulation of DSBs caused neutrophil-mediated genotoxicity, which resulted in induction of non-homologous end-joining (NHEJ). In turn, this allowed for increased growth and survival of advanced CRC.

Treatment of cultured HCT116 CRC cells with normal HR activity with clinically approved PARP1 inhibitor olaparib exerted no significant effect on the viability of cells. However, the investigators discovered a PMN-induced HR-deficient CRC phenotype that featured RAD51 and low Ku70 levels, ultimately making it more susceptible to synthetic lethality from olaparib.

Another distinct PMN-induced HR-deficient CRC phenotype was identified, which included high Ku70 and increased NHEJ. The researchers noted that this second phenotype can be targeted by non-HR inhibition.

A limitation of this study was the use of experiments performed on animal models and human tissue biopsies that were limited to only sporadic CRC. The investigators suggest that additional studies with human patients and other neutrophil-derived regulatory factors are needed.

The researchers added that their findings may likely “expand the therapeutic scope of FDA-approved olaparib and small-molecule inhibitors targeting NHEJ to CRC.”

Reference

Bui TM, Butin-Israeli V, Wiesolek HL, et al. Neutrophils alter DNA repair landscape to impact survival and shape distinct therapeutic phenotypes of colorectal cancer. Published online March 19, 2021. Gastroenterol. doi: 10.1053/j.gastro.2021.03.027