Protein kinase inhibitors and immune checkpoint inhibitors have revolutionized cancer treatment, but most cancer patients still do not respond due to multiple cancer pathways and immune cold tumor environment. Notably, ATRA (all transretinoic acid) and ATO (arsenic trioxide) have cured ~90% acute promyelocytic leukemia (APL) from its 90% lethality, but the underlying drug targets were elusive. Our first high throughput Pin1 drug screens have led to the unexpected discoveries that ATRA and ATO synergistically inhibit and degrade Pin1 to block numerous cancer pathways and to eliminate cancer stem cells in leukemias and solid tumors, as well as to overcome cancer resistance to chemotherapy, radiation therapy, targeted therapy, and immunotherapy (Nature Med 2015; Nature Commun 2018). For example, targeting Pin1 using ATRA+ATO or Pin1-specific inhibitor Sulfopin renders aggressive pancreatic cancer eradicable by immunochemotherapy for the first time (Cell 2021), with international clinical trials being planned.
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