Increasing the efficiency of targeted therapy in melanoma through CDKN1A/p21-dependent DNA damage response pathways

• Applicant: Professorin Dr. Birgit Schittek
• Subject Area: Dermatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560371414

Although the development of targeted therapies that inhibit the MAPK signaling pathway has improved the prognosis of melanoma patients, melanoma remains one of the most aggressive types of cancer with a high mortality rate. In particular, the development of resistance to MAPK inhibitors poses a major challenge. Furthermore, other treatment approaches, such as immunotherapeutic therapies with immune checkpoint inhibitors, only show a lasting response in around half of melanoma patients. Therefore, novel molecular approaches for targeting melanoma cells and identifying subgroups of patients who will benefit from targeted therapies are urgently needed. In our previous work, we demonstrated a synergistic effect of MAPK inhibitors with either MDM2 or PARP inhibitors in melanoma cells. We showed that MAPK inhibitors decrease the efficiency of homologous recombination repair. Interestingly, we found that the sensitivity towards these targeted therapies depends on high CDKN1A/p21 expression in melanoma cells. From these data we hypothesize that enhancing CDKN1A/p21 expression synergistically increase sensitivity towards MAPK inhibitors in melanoma by further decreasing homologous recombination repair efficiency and that CDKN1A/p21 expression can be used as a predictive biomarker for treatment response. Based on these data, we aim 1.to identify the molecular mechanisms of p21-induced enhancement of melanoma treatment response towards MAPK inhibitors 2.to test the benefit of p21 as a predictive biomarker for MAPK inhibitor sensitivity In our work program, we will use established in vitro and in vivo functional analyses with human melanoma cell lines and human 3D cell models as well as suitable mouse models and evaluate the clinical relevance of our results using patient material.

• DFG Programme: Research Grants