AI Article Synopsis
- - The study investigates how inhibiting the CDK4/6 gene can improve radiation treatment effectiveness in HPV(-) Oral Cavity Squamous Cell Carcinoma (OCSCC), which typically shows resistance to such treatments.
- - Various methods, including MTT assays and 3D growth models from patient tumors, were used to analyze the effects of combining radiation with the CDK4/6 inhibitor palbociclib, revealing reduced cell survival and increased signs of senescence and DNA damage.
- - Results suggest that targeting CDK4/6 not only enhances the response to radiation in OCSCC by promoting cellular aging but also disrupts the cancer cells' ability to repair DNA, potentially leading to better treatment outcomes.
Article Abstract
Purpose: HPV(-) OCSCC resists radiation treatment. The gene, encoding p16INK4A, is commonly disrupted in OCSCC. p16 inhibits CDK4/CDK6, leading to cell cycle arrest, but the biological sequelae of CDK4/6 inhibition in OCSCC remains understudied. This study examines whether inhibition of CDK4/6 enhances radiation response in OCSCC.
Methods: MTT assays were performed in OCSCC cell lines HN5 and CAL27 following treatment with palbociclib. Clonogenic survival and synergy were analyzed after radiation (RT-2 or 4Gy), palbociclib (P) (0.5 µM or 1 µM), or concurrent combination treatment (P+RT). DNA damage/repair and senescence were examined. CDK4/6 were targeted via siRNA to corroborate P+RT effects. Three-dimensional immortalized spheroids and organoids derived from patient tumors (conditionally reprogrammed OCSCC CR-06 and CR-18) were established to further examine and validate responses to P+RT.
Results: P+RT demonstrated reduced viability and synergy, increased β-gal expression (~95%), and ~two-fold higher γH2AX. Rad51 and Ku80 were reduced after P+RT, indicating impairment of HR and NHEJ. siCDK4/6 increased senescence with radiation. Spheroids showed reduced proliferation and size with P+RT. CR-06 and CR-18 further demonstrated three-fold reduced proliferation and organoids size with P+RT.
Conclusion: Targeting CDK4/6 can lead to improved efficacy when combined with radiation in OCSCC by inducing senescence and inhibiting DNA damage repair.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093103 | PMC |
| http://dx.doi.org/10.3390/cancers15072005 | DOI Listing |
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