WEE1 kinase inhibition to overcome acquired resistance to targeted therapies in colorectal cancer

ABSTRACT: Molecular therapies targeting the EGFR/MAPK pathway have improved outcomes in colorectal cancer (CRC), yet acquired resistance remains a major clinical challenge. Oncogenic signaling can activate stress response pathways that sustain tumor survival under therapeutic pressure. Among these, the DNA damage response (DDR) maintains genomic integrity and may represent a targetable vulnerability in resistant tumors. To investigate this, we developed a preclinical platform of CRC models with acquired resistance to anti-EGFR agents ("ARes platform"). A targeted pharmacological screen of DDR inhibitors identified WEE1 kinase as a leading therapeutic candidate. Validation in xenograft models and patient-derived organoids confirmed that anti-EGFR-resistant CRCs retained, and in some cases increased,

SUBMITTER: Kristi Buzo 

PROVIDER: S-SCDT-10_1038-S44321-026-00434-4 | biostudies-other |

REPOSITORIES: biostudies-other