Combined inhibition of STAT3 and DNA repair in palbociclib-resistant ER-positive breast cancer

The results from our study have identified two clinically relevant, divergent and druggable pathways (DNA repair and STAT3) that can be targeted in combination to effectively combat drug resistance. We also found that the same pathways that were deregulated in palbociclib-resistant cells were also altered in tumor samples obtained from patients who progressed while on palbociclib and endocrine therapy Overall design: Palbociclib resistant T47D cells were generated in a step-wise dose-escalading fashion. Whole-exome sequencing, genome-wide expression analysis and proteomic analysis were performed in both resistant and parental (sensitive) cells. Pathway alteration was assessed mechanistically and pharmacologically. Biomarkers of altered pathways were examined in tumor samples from palbociclib treated breast cancer patients whose disease progressed while on treatment.