Abstract LB516: MDM2/MDM4 amplification and CDKN2A deletion in melanoma brain metastases and GBM may have implications for targeted therapeutics and immunotherapy

Abstract

Abstract Melanoma has a five-year survival rate of 27% for distant metastatic disease, and there remains a paucity of targeted therapies for metastatic disease and biomarkers that predict metastasis to specific sites. We analyzed 1081 primary melanoma samples and 358 metastatic melanoma samples and found that metastatic disease is enriched for amplifications in both MDM2 and MDM4 compared to primary disease, and these amplifications are associated with a lower probability of overall survival. Two additional negative regulators of TP53, namely USP7 and PPM1D, are enriched for alterations in metastatic melanoma compared to primary melanoma. MDM4 amplifications are associated with a higher rate of metastasis to the brain, liver, and lungs, while MDM2 amplifications are associated with a higher rate of metastasis to the brain, liver, and adrenal glands. These findings suggest that patients with metastatic melanoma show an enhanced dysregulation of the TP53 pathway compared to primary disease; though still under ongoing preclinical evaluation to assess therapeutic implications, we propose that patients with metastatic melanoma and TP53 wild-type status may be more likely to benefit from MDM2, MDM4, USP7, and PPM1D inhibitors, both alone and in combination, compared to those with primary disease. Additionally, we found that patients with MDM2 alterations were more likely to have a deep deletion in CDKN2A, alterations that are also associated with a higher rate of metastasis to the brain. We found that patients with a CDKN2A deep deletion had a statistically significant higher rate of alterations in TTN, MUC16, LRP1B, NF1, and SERPINB4, alterations that have all been previously associated with a favorable response to immune checkpoint inhibitors in melanoma. We therefore propose that CDKN2A deletion may serve as a biomarker to predict response to immunotherapy in melanoma. Moreover, given prior documented cases of patients diagnosed with both melanoma and glioblastoma multiforme (GBM), we found that GBM displays the highest rate of deep deletions in CDKN2A (54.39%) across all cancer types screened. We analyzed 619 GBM samples and found that 9.16% display an MDM2 amplification and 9.52% display an MDM4 amplification. Given the genomic similarities between melanoma and glioblastoma, we suggest that patients with melanoma or GBM and amplifications in MDM2/4 and CDKN2A deletions may need the development of combinations of targeted inhibitors of MDM2/4, CDK’s and immunotherapy. We are currently pursuing these translational directions. Citation Format: Taylor E. Arnoff, Wafik S. El-Deiry. MDM2/MDM4 amplification and CDKN2A deletion in melanoma brain metastases and GBM may have implications for targeted therapeutics and immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB516.