Our study highlights the cis-acting regulatory features underlying susceptibility to transcriptional and post-transcriptional variations induced by splicing-targeting drugs; it reveals IR as the prominent pattern induced by both direct (Ind/PlaB) and indirect (THZ531) inhibition of splicing and uncovers the 3’-end mRNA processing as a druggable vulnerability for advanced PC. The gene discussed is GDF15; the disease is pachyonychia congenita.