Rewiring glucose metabolism improves 5-FU efficacy in p53-deficient/KRASG12D glycolytic colorectal tumors

TY - JOUR

T1 - Rewiring glucose metabolism improves 5-FU efficacy in p53-deficient/KRASG12D glycolytic colorectal tumors

AU - Ludikhuize, Marlies C

AU - Gevers, Sira

AU - Nguyen, Nguyen T B

AU - Meerlo, Maaike

AU - Roudbari, S Khadijeh Shafiei

AU - Gulersonmez, M Can

AU - Stigter, Edwin C A

AU - Drost, Jarno

AU - Clevers, Hans

AU - Burgering, Boudewijn M T

AU - Rodríguez Colman, Maria J

N1 - © 2022. The Author(s).

PY - 2022/10/31

Y1 - 2022/10/31

N2 - Despite the fact that 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), the response rates in patients is limited to 50%. The mechanisms underlying 5-FU toxicity are debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic heterogeneity, relate to the 5-FU response remains obscure. This largely relies on the limited number of studies performed in pre-clinical models able to recapitulate the key features of CRC. Here, we analyzed the 5-FU response in patient-derived organoids that reproduce the different stages of CRC. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death in the actively proliferating cancer cells deficient in p53. Importantly, p53-deficiency leads to cell death due to impaired cell cycle arrest. Moreover, we find that targeting the Warburg effect in KRASG12D glycolytic tumor organoids enhances 5-FU toxicity by further altering the nucleotide pool and, importantly, without affecting non-transformed WT cells. Thus, p53 emerges as an important factor in determining the 5-FU response, and targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

AB - Despite the fact that 5-fluorouracil (5-FU) is the backbone for chemotherapy in colorectal cancer (CRC), the response rates in patients is limited to 50%. The mechanisms underlying 5-FU toxicity are debated, limiting the development of strategies to improve its efficacy. How fundamental aspects of cancer, such as driver mutations and phenotypic heterogeneity, relate to the 5-FU response remains obscure. This largely relies on the limited number of studies performed in pre-clinical models able to recapitulate the key features of CRC. Here, we analyzed the 5-FU response in patient-derived organoids that reproduce the different stages of CRC. We find that 5-FU induces pyrimidine imbalance, which leads to DNA damage and cell death in the actively proliferating cancer cells deficient in p53. Importantly, p53-deficiency leads to cell death due to impaired cell cycle arrest. Moreover, we find that targeting the Warburg effect in KRASG12D glycolytic tumor organoids enhances 5-FU toxicity by further altering the nucleotide pool and, importantly, without affecting non-transformed WT cells. Thus, p53 emerges as an important factor in determining the 5-FU response, and targeting cancer metabolism in combination with replication stress-inducing chemotherapies emerges as a promising strategy for CRC treatment.

KW - Humans

KW - Tumor Suppressor Protein p53/genetics

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

KW - Fluorouracil/pharmacology

KW - Colorectal Neoplasms/drug therapy

KW - Glucose

U2 - 10.1038/s42003-022-04055-8

DO - 10.1038/s42003-022-04055-8

M3 - Article

C2 - 36316440

SN - 2399-3642

VL - 5

SP - 1159

JO - Communications Biology

JF - Communications Biology

IS - 1

ER -