In conclusion, a deep understanding of splicing-driven drug resistance mechanisms, a novel synergistic strategy combining PI3K and SRPK1/2 inhibitors, and further screening/designing novel compounds targeting PI3Kδ-S may pave a new path for precision medicine for resistant AA PCa and other hematologic/non-hematologic tumors overexpressing PIK3CD-S. Here, SRPK1 is linked to posterior cortical atrophy.