Spheroid-enriched cancer stem-like cells as a model for targeted therapy in oral cancer with distal 11Q loss

[摘要] Oral squamous cell carcinoma (OSCC) has a poor prognosis due to multiple factors including local recurrence, distant metastasis and therapeutic resistance. Our laboratory has demonstrated that the ATR-CHEK1 pathway is a critical modulator of radioresistance in OSCC; we evaluated the effectiveness of targeted CHEK1 inhibition in OSCC cancer stem-like cells (CSLC). To this end, we analyzed CSLC properties and the effect of ionizing radiation (IR) and CHEK1 inhibition on CSLCs isolated from OSCC (parental) cell lines with and without distal 11q loss. The CSLCs, propagated in enriched serum-free medium, demonstrated stem-cell like characteristics including asymmetrical and symmetrical cell division, self-renewal, re-differentiation, colony forming capacity at extreme (limiting) dilutions, and radioresistance. CHEK1 inhibitors affected the functional CSLC properties, resulting in significant reduction in proliferation, survival, colony initiation, growth, migration. The most drastically affected CSLC property was extracellular matrix migration. As determined by dose-response curves, a drug level ≈100-fold higher than the dose that was effective on parental OSCC cell lines was required to inhibit CSLC migration.Overall, our results suggest that distal 11q loss may predict radioresistance in CSLC; however, the CSLC response to IR-CHEK1 inhibition is not distal 11q loss-driven. CHEK1 inhibitors increase the radiosensitivity of oral CSLC as they do for OSCC cell lines. Thus, we propose that CHEK1 inhibition may be a useful adjuvant therapy for advanced and/or metastatic OSCC.PUBLIC HEALTH SIGNIFICANCE: Our results increased the understanding of cancer stem-like cells in oral cancers and establish these cells as a contributing factor to radioresistance that could be potentially reversed in as many as 25% of cancers by CHEK1 inhibitors.

[发布机构] the University of Pittsburgh