Our proposed computational framework is able to predict putative cross-talks among signaling pathways that play a role in drug resistance in two breast cancer cell-lines, SKBR3 and BT474. Our framework could also be useful for other types of cancer to enhance understanding of the role of signaling cross-talks in drug resistance. Most importantly, we believe our method can be used to find a range of compensatory pathways that nullify/reduce the inhibiting effects of drugs via cross-talk with targeted pathways. These novel compensatory pathways can be further considered as novel targets for single or combination therapies.