TY - JOUR
T1 - Targeting mutant RAS in patient-derived colorectal cancer organoids by combinatorial drug screening
AU - Verissimo, Carla S
AU - Overmeer, René M
AU - Ponsioen, Bas
AU - Drost, Jarno
AU - Mertens, Sander
AU - Verlaan-Klink, Ingrid
AU - Gerwen, Bastiaan van
AU - van der Ven, Marieke
AU - Wetering, Marc van de
AU - Egan, David A
AU - Bernards, René
AU - Clevers, Hans
AU - Bos, Johannes L
AU - Snippert, Hugo J
N1 - Publisher Copyright:
© Verissimo et al.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic KRAS mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that are currently in clinical trial for RAS mutant cancers. Presence of mutant RAS correlated strongly with resistance to these targeted therapies. This was observed in tumorigenic as well as in normal organoids. Moreover, dual inhibition of the EGFR-MEK-ERK pathway in RAS mutant organoids induced a transient cell-cycle arrest rather than cell death. In vivo drug response of xenotransplanted RAS mutant organoids confirmed this growth arrest upon pan-HER/MEK combination therapy. Altogether, our studies demonstrate the potential of patient-derived CRC organoid libraries in evaluating inhibitors and drug combinations in a preclinical setting.
AB - Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic KRAS mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that are currently in clinical trial for RAS mutant cancers. Presence of mutant RAS correlated strongly with resistance to these targeted therapies. This was observed in tumorigenic as well as in normal organoids. Moreover, dual inhibition of the EGFR-MEK-ERK pathway in RAS mutant organoids induced a transient cell-cycle arrest rather than cell death. In vivo drug response of xenotransplanted RAS mutant organoids confirmed this growth arrest upon pan-HER/MEK combination therapy. Altogether, our studies demonstrate the potential of patient-derived CRC organoid libraries in evaluating inhibitors and drug combinations in a preclinical setting.
KW - Antineoplastic Agents/isolation & purification
KW - Clustered Regularly Interspaced Short Palindromic Repeats
KW - Colorectal Neoplasms/drug therapy
KW - Drug Evaluation, Preclinical/methods
KW - Humans
KW - Mutant Proteins/antagonists & inhibitors
KW - Organoids/drug effects
KW - Recombination, Genetic
KW - ras Proteins/antagonists & inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85001075487&partnerID=8YFLogxK
U2 - 10.7554/eLife.18489
DO - 10.7554/eLife.18489
M3 - Article
C2 - 27845624
SN - 2050-084X
VL - 5
JO - eLife
JF - eLife
IS - NOVEMBER2016
M1 - e18489
ER -