YAP/TEAD4-reagulated placental alkaline phosphatases ALPP and ALPPL2 are immunosuppressive ectonucleotidases modulated by MAPK inhibitors

Bauche, D.; Martin, J. L.; Huang, B.; Ehrenberger, T.; Hasan, A. R.; Dow, M.; Khoo, W. H.; Pacaud, R.; Metwally, E.; Porth, K.; Kim, G.; McKenna, S.; Li, C.; Ho, N.; Nguyen, K.; Hahn, S.; Rath, B.; sathiyamoorthy, K.; Ho, s. w. s.; Yang, P.; Olow, A.; Sadekova, S.

doi:10.1101/2025.10.15.682438

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bioRxiv · 10.1101/2025.10.15.682438

YAP/TEAD4-reagulated placental alkaline phosphatases ALPP and ALPPL2 are immunosuppressive ectonucleotidases modulated by MAPK inhibitors

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Abstract

Placental alkaline phosphatases ALPP and ALPPL2 (ALPP/L2) are promising clinical targets for therapies such as antibody-drug conjugates (ADCs). However, their regulation and biological functions remain unclear. Here, we identify the YAP/TEAD4 signaling axis as the primary regulator of ALPP/L2 expression in tumor cells. Importantly, we demonstrate that inhibitors targeting KRAS, MEK, and ERK upregulate ALPP/L2 expression in vitro and in vivo, thereby enhancing the efficacy of antibody-drug conjugates (ADCs) when used in combination. Moreover, our work reveals a novel immunomodulatory function of ALPP/L2 as cell surface ectonucleotidases that hydrolyze extracellular ATP, ADP, and AMP to adenosine, promoting regulatory T cell infiltration into the tumor microenvironment. Together, these findings reveal a biological function of ALPP/L2 and identify druggable regulators to enhance ALPP/L2-targeted therapies. SIGNIFICANCEThis study uncovers the YAP/TEAD pathway as a positive regulator of the clinically relevant tumor-associated antigens ALPP and ALPPL2. Kras, MEK, or ERK inhibitors enhance ALPP/L2 expression in tumor cells, thereby increasing the efficacy of ALPP/L2-targeted antibody-drug conjugates. These findings offer a promising combination strategy to overcome resistance to ALPP/L2-based therapies caused by low target expression.

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Bauche, D., Martin, J. L., Huang, B., Ehrenberger, T., Hasan, A. R., Dow, M., Khoo, W. H., Pacaud, R., Metwally, E., Porth, K., Kim, G., McKenna, S., Li, C., Ho, N., Nguyen, K., Hahn, S., Rath, B., sathiyamoorthy, K., Ho, s. w. s., Yang, P., Olow, A., Sadekova, S.. 2025-10-15. YAP/TEAD4-reagulated placental alkaline phosphatases ALPP and ALPPL2 are immunosuppressive ectonucleotidases modulated by MAPK inhibitors. https://doi.org/10.1101/2025.10.15.682438

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