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Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon
Sander Mertens1, Maarten A Huismans1, Carla S Verissimo1
1Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
Abstract:
Patient-derived organoids (PDOs) are widely heralded as a drug-screening platform to develop new anti-cancer therapies. Here, we use a drug-repurposing library to screen PDOs of colorectal cancer (CRC) to identify hidden vulnerabilities within therapy-induced phenotypes. Using a microscopy-based screen that accurately scores drug-induced cell killing, we have tested 414 putative anti-cancer drugs for their ability to switch the EGFRi/MEKi-induced cytostatic phenotype toward cytotoxicity. A majority of validated hits (9/37) are microtubule-targeting agents that are commonly used in clinical oncology, such as taxanes and vinca-alkaloids. One of these drugs, vinorelbine, is consistently effective across a panel of >25 different CRC PDOs, independent of RAS mutational status. Unlike vinorelbine alone, its combination with EGFR/MEK inhibition induces apoptosis at all stages of the cell cycle and shows tolerability and effective anti-tumor activity in vivo, setting the basis for a clinical trial to treat patients with metastatic RAS-mutant CRC.
Insights
Patient-derived organoids (PDOs) identified microtubule-targeting agents, like vinorelbine, as effective in treating colorectal cancer (CRC). Combining vinorelbine with EGFR/MEK inhibitors shows promise for metastatic RAS-mutant CRC.
Area of Science:
- Oncology
- Drug Discovery
- Cancer Research
Background:
- Patient-derived organoids (PDOs) are valuable for anti-cancer drug screening.
- Colorectal cancer (CRC) presents challenges in developing effective therapies.
- Identifying novel therapeutic vulnerabilities is crucial for CRC treatment.
Purpose of the Study:
- To screen a drug-repurposing library against CRC PDOs.
- To identify drugs that convert cytostatic to cytotoxic phenotypes under EGFR/MEK inhibition.
- To find novel therapeutic strategies for colorectal cancer.
Main Methods:
- Utilized a microscopy-based screen to assess drug-induced cell killing in CRC PDOs.
- Tested 414 anti-cancer drugs for their efficacy in combination with EGFR/MEK inhibitors.
- Evaluated the effectiveness of identified hits, including vinorelbine, across multiple CRC PDO models.
Main Results:
- A majority of validated hits (9/37) were microtubule-targeting agents (e.g., taxanes, vinca-alkaloids).
- Vinorelbine demonstrated consistent efficacy across >25 CRC PDOs, irrespective of RAS mutation status.
- The combination of vinorelbine with EGFR/MEK inhibition induced apoptosis and showed anti-tumor activity in vivo.
Conclusions:
- Microtubule-targeting agents represent a promising class of drugs for CRC therapy.
- Vinorelbine, in combination with EGFR/MEK inhibitors, offers a potential treatment for metastatic RAS-mutant CRC.
- This combination therapy warrants further investigation in clinical trials.
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