102P - Colorectal cancer organoids culture exploits new neoadjuvant therapy resistance mechanisms and therapeutic targets

Background

Tumor organoids are a state of the art platform for precision medicine. With more and more studies showing that the treatment in organoids in vitro perfectly matches the patients' response, tumor organoids could predict patients' responses in clinical settings, including for colorectal cancer, pancreatic cancer, and ovarian cancer. Based on these studies, comparing the genetic data from the tumor organoids should be a strategy to investigate treatment resistance mechanisms and exploit new therapeutic targets.

Methods

Tumor organoids were obtained from our colorectal cancer organoids bank. RNA sequencing analysis was used to screen potential markers that play pivotal roles in mediating treatment response based on the organoids' response to drug treatment and radiation. Candidate genes were analyzed by qPCR, and CRISPR technology was applied to investigate the gene function in cell lines and organoids.

Results

We found several differentially expressed genes between sensitive and resistant organoid groups of which most were metabolism related. Among them, GPX2 and FREM1 were highly expressed in colorectal cancer and could prompt cell proliferation and growth. GPX2 and FREM1 are found to tightly influence treatment with 5-FU and irinotecan, respectively, in colorectal cancer cells, higher GPX2 could enhance the IC50 of 5-FU, while FREM1 increases the IC50 of irinotecan in colorectal cancer cells, and both of them could increase radiation resistance. Overexpressing GPX2 could decrease cellular ROS levels, increase stem cell marker CD24 level and EMT transition, while FREM1 could activate the NF-KB signaling and inhibit cell apoptosis included by radiation and drug treatment.

Conclusions

Tumor organoids could be useful to explore new therapeutic targets in cancer treatment with higher precision. GPX2 and FREM1 which are upregulated in colorectal cancer increase cell proliferation and growth, cause radioresistance. GPX2 is related to 5-FU resistance while FREM1 is related to irinotecan resistance in colorectal cancer cells. These results imply these two molecules could be new therapeutic targets in the treatment of colorectal cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Zhen Zhang.

Funding

National Natural Science Foundation of China, 81773357.

Disclosure

All authors have declared no conflicts of interest.