Overcoming Resistance to Targeted Therapies in Gastrointestinal Cancers: Progress to Date and Progress to Come.

Targeted therapies have transformed the treatment paradigm in diseases such as non-small cell lung cancer and melanoma but have shown relatively modest clinical benefit in gastrointestinal malignancies. Anti-EGFR therapy in wild-type colorectal cancer, anti-HER2 therapy in - amplified esophagogastric cancer, and FGFR and isocitrate dehydrogenase 1 (IDH1) inhibitors in fusion-positive and mutant biliary tract cancers offer antitumor efficacy, but the clinical benefit and durability of response in each case are typically limited. We review targeted therapies in each of these therapeutic areas and discuss their clinical efficacy, mechanisms of primary and acquired resistance, and strategies to overcome this resistance. We discuss lessons learned that we hope will lead to an expanded role for molecularly targeted therapy options for patients with gastrointestinal cancers.