Abstract
Background Lack of expression of the transcription factor CDX2 identifies a subset of poorly differentiated colorectal cancers (CRCs) that are associated with lower overall (OS) and disease-free (DFS) survival, independent of ethnicity, MSI status, or stage. Reinstatement of CDX2 is predicted to lower the risk of death and recurrence by 50% but such a therapeutic strategy is yet to emerge.
Methods A network-based computational model, validated using healthy colon and CRC tissues in diverse gene expression datasets (~5,000 human and >300 mouse samples), was used to identify therapeutic targets that can augment CDX2 expression. The top candidate with available clinical-grade drug (PRKAB1) was tested on 3 models: CRC lines in vitro, xenografts in mice, and in a prospective cohort of healthy (n = 3) and CRC (n = 23) patient-derived organoids (PDOs).
Results In all 3 models, PRKAB1-agonism predictably shifted the network, induced CDX2 and crypt differentiation signatures and showed selective cytotoxicity towards CDX2-negative CRCs. Xenotransplantation studies in mice reduced tumour volume by 68% and abolished mortality (Hazard ratio; H.R = 0.09). Effective pairing of therapeutic efficacy (IC50 for PRKAB1-agonism) and biomarker (CDX2-low state) was validated in an independent cohort of PDOs. A multivariate analysis revealed CDX2-low state as the key determinant of therapeutic efficacy. A 50-gene signature of therapeutic response tested on 9 cohorts (n = 1701 patients) showed that CDX2-reinstatement therapy will reduce the risk of mortality/recurrence by ~50%.
Conclusions CDX2-reinstatement therapy selectively triggers cell differentiation and death in CDX2-low CRCs. Realization of the benefit of such therapy-biomarker pairing requires confirmatory studies in randomized clinical trials.
Competing Interest Statement
The authors have declared no competing interest.
