Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer

TY - JOUR

T1 - Drug-repurposing screen on patient-derived organoids identifies therapy-induced vulnerability in KRAS-mutant colon cancer

AU - Mertens, Sander

AU - Huismans, Maarten A

AU - Verissimo, Carla S

AU - Ponsioen, Bas

AU - Overmeer, Rene

AU - Proost, Natalie

AU - van Tellingen, Olaf

AU - van de Ven, Marieke

AU - Begthel, Harry

AU - Boj, Sylvia F

AU - Clevers, Hans

AU - Roodhart, Jeanine M L

AU - Bos, Johannes L

AU - Snippert, Hugo J G

N1 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2023/4/25

Y1 - 2023/4/25

N2 - 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.

AB - 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.

KW - Humans

KW - Proto-Oncogene Proteins p21(ras)/metabolism

KW - Colorectal Neoplasms/drug therapy

KW - Vinorelbine/pharmacology

KW - Drug Repositioning

KW - Cell Line, Tumor

KW - Colonic Neoplasms/drug therapy

KW - Antineoplastic Agents/pharmacology

KW - Organoids/metabolism

U2 - 10.1016/j.celrep.2023.112324

DO - 10.1016/j.celrep.2023.112324

M3 - Article

C2 - 37000626

SN - 2211-1247

VL - 42

SP - 112324

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -