Targeting the PI3K/AKT/mTOR pathway in gastrointestinal cancers: a comprehensive review of mechanisms, preclinical evidence, and clinical challenges.

Gastrointestinal (GI) cancers encompass malignant conditions of the GI tract and accessory digestive organs, including the esophagus, gastric cancer (GC), biliary system, hepatocellular carcinoma (HCC), pancreatic cancer (PC), and colorectal cancer (CRC). Globally, CRC ranks as the third most commonly diagnosed cancer, with gastric, hepatic, and esophageal cancers following in fifth, sixth, and seventh places, respectively. PC contributes notably to cancer mortality, ranking 12th in incidence and 7th in mortality. Despite major advances in diagnosis and treatment, GI cancers remain among the most aggressive malignancies and continue to drive substantial global morbidity and mortality. In 2020, GI cancers accounted for more than 4.8 million new cases and 3.4 million deaths. Although early-stage GI tumors can be surgically resected with curative intent, the overall 5-year relapse rate remains high. Neoadjuvant or adjuvant chemotherapy and radiotherapy provide only modest long-term survival improvements when applicable. In recent decades, prognosis for advanced GI cancers has improved due to tailored therapies that combine cytotoxic and targeted agents and integrate systemic treatments with more effective surgical and locoregional approaches. Nevertheless, GI malignancies remain a leading cause of cancer death, underscoring the need for novel therapeutic options. A central molecular driver is the PI3K/AKT/mTOR signaling axis, which governs chemotherapy resistance, metastasis, survival, metabolism, and growth, and modulates the tumor microenvironment via angiogenesis and inflammatory infiltration. Dysregulation of this axis is common across GI cancers, guiding exploration of pathway-targeted therapies, alone or in combination. Although several agents show promise, toxicities such as neuropsychiatric effects, diarrhea, hepatotoxicity, and hyperglycemia limit clinical utility. Therefore, refined personalization and combination strategies targeting PI3K/AKT/mTOR are critical to improving efficacy and reducing resistance in GI malignancies.