Tumor Organoids Can Help Overcome Therapy Resistance of Colorectal Cancer

Driven by genetic mutations, but also in reaction to their micro-environment, tumors go through a constant development from the very first moment. Chemotherapeutic stress in particular intensifies and accelerates this process. In the course of this therapy-driven tumor evolution, treatment resistance often develops and the initial treatment strategy fails.

In order to better understand the evolution of colorectal cancer and the resulting development of therapy resistance, scientists at the DKTK partner site in Munich have now grown patient-specific mini-tumors, so-called colorectal cancer organoids, in the culture dish. Such patient-specific tumor organoids can often be used to predict the efficacy of drugs. They are therefore considered an important tool in personalized cancer medicine. For their project, the researchers used material from intestinal tumors that had already spread to the liver. The tumor organoids grown from this material were exposed to typical clinical combination chemotherapy for a prolonged period of time until therapy resistance occurred.

During thorough molecular analysis of the now "chemotolerant" organoids, the DKTK team discovered that the cancer cells undergo different patterns of genetic evolution during their adaptation to therapy, depending on their individual background. As a result, they also respond differently to second-line therapies.

Often, after developing resistance to the first chemotherapy, the researchers found elevated levels of the oncoprotein c-MYC, which strongly promotes tumor cell growth and survival. Using the CRISPR/Cas9 gene scissors, they were also able to insert a mutation in the KRAS oncogene that is known to be extremely problematic clinically and determine its impact on the resistance of tumor organoids to therapy.

Based on these results, the DKTK team developed strategies for a combination therapy that can overcome the acquired chemotherapy resistance of colorectal cancer cells. Simultaneous suppression of several signaling pathways that play key roles in different phases of the cell cycle of colorectal cancer cells proved to be very promising.

Initially, the therapy-resistant tumor organoids were no longer able to induce programmed cell death apoptosis and thus continued growing almost unhindered. The new combined therapeutic approach, however, enabled the cells to restart the cell death program and initiate their own death. The growth of the mini-tumors was almost completely stopped by the combination therapy.

The result shows that patient-specific tumor organoids have great potential in optimizing and possibly adapting targeted chemotherapeutic treatment strategies against colon cancer. It also underscores the overall importance of organoid platforms for personalized cancer medicine.

Publication: Sophie L. Boos, Leon P. Loevenich, Sebastian Vosberg, Thomas Engleitner, Rupert Öllinger, Jörg Kumbrink, Matjaz Rokavec, Marlies Michl, Philipp A. Greif, Andreas Jung, Heiko Hermeking, Jens Neumann, Thomas Kirchner, Roland Rad, Peter Jung. Disease modeling on tumor organoids implicates AURKA as a 1therapeutic target in liver metastatic colorectal cancer. Cellular and Molecular Gastroenterology and Hepatology (CMGH) 2021, DOI: https://doi.org/10.1016/j.jcmgh.2021.10.008