Circadian disruption in colorectal cancer: Promise of chronotherapy as precision medicine

Circadian disruption promotes colorectal cancer (CRC) at multiple levels that could address CRC-treatment challenges like late detection, tumour heterogeneity and therapeutic resistance. Therefore, chronodisruption-CRC axis gains tremendous research attention. This review illustrates well-rounded mechanistic details and therapeutic perspective of the domain. Deregulated expressions of core clock genes (BMAL1, CLOCK, CRY, PER) disrupt crucial cellular processes like cell cycle control, DNA-repair and apoptotic regulation. They are associated with key CRC signaling pathways Wingless-related integration site (Wnt)/β-catenin, Phosphoinositide 3-kinase/Protein kinase B/Mechanistic target of rapamycin (PI3K/AKT/mTOR) and Notch signaling. Circadian disruption shows immunosuppression in CRC-model. Further, disrupted intestinal clock alters gut microbial distribution (dysbiosis) and impairs intestinal barrier function in CRC. Chronological misalignment contributes to both intratumoral and intertumoral heterogeneity in CRC tumors. Deregulated expressions of clock genes are recognized as prognostic biomarkers for CRC, and their association in the mechanism of chemo- and/or radio-resistance has been reported for CRC. Clinical evidences indicate that the optimized application of chemo- and/or radio-therapies based on individual's biological clock improves treatment efficacy and reduces toxicity in CRC patients at the advanced stage. Therefore, chronotherapy through complementary approaches like "training the clock" (e.g., dietary restriction, light exposure), "drugging the clock" (e.g., REV-ERB agonists), and "clocking the drug" could represent a promising integrated strategy for precision medicine in CRC. The review explicitly elucidates the molecular mechanisms through which chronodisruption contributes to colorectal carcinogenesis and explores the prospect of chronotherapy as precision medicine for CRC. Future direction emphasizes on refining individualized chronotherapy protocols in multicentric randomized controlled trials.