Tumor heterogeneity and lack of knowledge about resistant cell states remain significant barriers to effective targeted cancer therapies. Basal cell carcinomas (BCCs) uniformly depend on Hedgehog (Hh)/Gli signaling for cell growth. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies Gli1 activity, but definition of the nMRTF cell state, key factors driving its accumulation, and a therapeutic strategy targeting this cancer cell state, remain unknown. Here, we use single cell sequencing of patient tumors to demonstrate that the nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, and identify three surface markers (LYPD3, TACSTD2, and LY6D) which reliably correlate with activity and serve as robust biomarkers to highlight Smo-inhibitor-resistant tumor cell populations. Epigenetic analysis of isolated nMRTF human tumor subpopulations demonstrates that cooperative AP-1 and TGFß signaling drive nMRTF activation. Mechanistically, JunD/AP-1 signaling drives changes in chromatin accessibility leading to differential Smad3 DNA binding and a transcriptional program of upstream activators of Rho, including RhoGEFs that facilitate nMRTF activity. Importantly, we observe that small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/ LY6D+ nMRTF human BCCs explants. Overall our work for the first time defines tumor subpopulations based on sensitivities, opening an avenue for improved combinatorial therapies.