Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy

• Advanced gallbladder cancer has poor prognosis and inherent resistance to adjuvant therapy.
• The genetic and epigenetic alterations play an important role in gallbladder carcinogenesis.
• Emergent signaling pathways in GBC must be explored in order to design rational therapies.
• The use the inhibitors of oncogenic pathways is a promising therapeutic alternative in GBC.

Gallbladder cancer is the most common and aggressive malignancy of the biliary tract. The complete surgical resection is the only potentially curative approach in early stage; however, most cases are diagnosed in advanced stages and the response to traditional chemotherapy and radiotherapy is extremely limited, with modest impact in overall survival. The recent progress in understanding the molecular alterations of gallbladder cancer has shown great promise for the development of more effective treatment strategies. This has mainly resulted from the identification of molecular alterations in relevant intracellular signaling pathways—Hedgehog, PI3K/AKT/mTOR, Notch, ErbB, MAPK and angiogenesis—which are potential tailored targets for gallbladder cancer patients. This review discusses the recent remarkable progress in understanding the molecular alterations that represent novel prognosis molecular markers and therapeutic targets for gallbladder cancer, which will provide opportunities for research and for developing innovative strategies that may enhance the benefit of conventional chemotherapy, or eventually modify the fatal natural history of this orphan disease.