A Pathway to Chordoma Treatment: A Review on CDKN2A and Therapeutic Targeting

Background: Chordoma is a rare malignant bone tumor thought to arise from remnants of the embryonic notochord. Its management remains challenging because of its proximity to critical neurovascular structures and its high propensity for local recurrence. Current standard treatment consists of maximal safe resection followed by radiotherapy, yet durable disease control remains difficult to achieve in many patients. Emerging evidence suggests that cyclin-dependent kinase inhibitor 2A (CDKN2A) loss is a recurrent molecular event in chordoma and may serve as both a prognostic biomarker and a therapeutic target. Methods: A literature search was performed by acquiring articles containing “(CDKN2A or p16) AND (chordoma or notochordal tumor)”, and “chordoma 9p21”. Of the 41 articles retrieved, 17 met the inclusion criteria. Results: Homozygous and heterozygous CDKN2A deletions were frequently identified in chordoma using fluorescence in situ hybridization and genomic sequencing approaches. These alterations were commonly associated with loss of p16^INK4A expression, the protein product of CDKN2A, supporting a role in tumorigenesis and disease progression. Epigenetic mechanisms may also contribute to reduced p16^INK4A expression in a subset of tumors. Preclinical studies in CDKN2A-deficient chordoma cell lines and patient-derived xenografts demonstrated sensitivity to cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including palbociclib, flavopiridol, and abemaciclib. Combination strategies pairing palbociclib with buparlisib or rapamycin produced greater antitumor effects, particularly in p16^INK4A- and PTEN-deficient models. In addition, CDKN2A loss has been associated with adverse clinical features in selected cohorts, although its independent prognostic significance remains unclear. Available preclinical evidence further suggests that chordomas lacking p16^INK4A expression and retaining retinoblastoma pathway dependence may be particularly susceptible to CDK4/6 inhibition. Conclusions: CDKN2A loss is a recurrent molecular alteration in chordoma that is associated with reduced p16^INK4A expression, adverse clinicopathologic features, and less favorable outcomes in selected cohorts, although its independent prognostic significance remains inconsistent. Preclinical data support CDK4/6 inhibition, particularly in biomarker-selected CDKN2A-deficient tumors, and suggest that combination approaches targeting complementary pathways such as PI3K/mTOR may further enhance therapeutic efficacy. Together, these findings support the clinical relevance of CDKN2A as both a prognostic biomarker and a promising therapeutic target in chordoma.