PI3K/AKT/mTOR Pathway Emerges as Central Target in Gastrointestinal Cancers

Gastrointestinal cancers remain among the most lethal malignancies in the world, and a newly published comprehensive review in Medical Oncology argues that a single signaling axis may hold the key to finally changing that trajectory. The review, led by Faride Kaikavoosnejad and colleagues at Kashan University of Medical Sciences, synthesizes the molecular mechanisms, preclinical evidence, and clinical experience accumulated over two decades of targeting the PI3K/AKT/mTOR pathway in tumors of the esophagus, stomach, biliary system, liver, pancreas, and colorectum. Its central message is sobering but constructive: the biology is compelling, the preclinical data are encouraging, yet the clinical translation has been repeatedly frustrated by toxicity and the absence of rigorous molecular patient selection.

The scale of the problem the review addresses is enormous. In 2020 alone, gastrointestinal cancers accounted for more than 4.8 million new cases and 3.4 million deaths worldwide. Colorectal cancer ranks as the third most commonly diagnosed cancer globally, with gastric, hepatic, and esophageal cancers following in fifth, sixth, and seventh places respectively. Pancreatic cancer, though only twelfth in incidence, is seventh in mortality, a grim reflection of its aggressive biology and late detection. Even when early-stage tumors can be surgically resected with curative intent, five-year relapse rates remain high, and neoadjuvant or adjuvant chemotherapy and radiotherapy deliver only modest long-term survival gains. The authors argue that this persistent therapeutic ceiling makes the search for actionable molecular drivers a matter of urgency rather than academic curiosity.

At the heart of that search sits the PI3K/AKT/mTOR cascade, a signaling highway that connects growth factor receptors on the cell surface to the core machinery of cell growth, metabolism, survival, and proliferation. When extracellular signals activate receptor tyrosine kinases such as EGFR or HER2, phosphoinositide 3-kinase generates lipid second messengers that recruit AKT to the membrane, where it is phosphorylated and activated. AKT then relays signals to mTOR, a kinase existing in two functionally distinct complexes, mTORC1 and mTORC2, that together regulate protein synthesis, autophagy, lipid metabolism, and angiogenesis. The review emphasizes that this axis governs chemotherapy resistance, metastatic dissemination, cell survival, metabolic reprogramming, and tumor growth, while also shaping the tumor microenvironment through the promotion of angiogenesis and inflammatory immune cell infiltration.

Dysregulation of this pathway is strikingly common across gastrointestinal malignancies. Somatic mutations in PIK3CA, the gene encoding the p110alpha catalytic subunit of PI3K, were first identified at high frequency in human cancers by Samuels and colleagues in a landmark 2004 Science paper, and subsequent studies confirmed their prevalence in gastric and colon tumors. In esophageal squamous cell carcinoma, PIK3CA mutations have been associated with worse patient outcomes. In gastric cancer, the pathway is frequently activated not only through PIK3CA mutation but also through loss of the negative regulator PTEN, HER2 amplification, and epigenetic mechanisms including long non-coding RNAs and microRNAs that modulate pathway components. In hepatocellular carcinoma, members of the PI3K/AKT/mTOR pathway and eukaryotic translation initiation factors have been proposed as novel biomarkers, while in pancreatic cancer, intrinsic PI3Kalpha activity has been shown to accelerate metastasis and rewire the macrophage composition of the tumor microenvironment.

The mechanistic detail matters because it explains why the pathway is such an attractive drug target. mTORC1, acting through its downstream effectors p70S6K and 4E-BP1, controls the translational landscape of the cell, steering cancer initiation and metastasis by selectively boosting the synthesis of mRNAs encoding growth and survival proteins. AKT phosphorylation of downstream targets suppresses apoptosis and promotes glucose uptake and glycolysis, feeding the metabolic appetite of rapidly dividing tumors. PI3K signaling also drives the expression of vascular endothelial growth factor and proangiogenic cytokines such as interleukin-8, linking pathway activation directly to the blood supply that tumors need to expand. Blocking any node in this cascade should, in principle, starve the cancer of multiple survival advantages simultaneously.

Preclinical evidence reviewed by the authors bears this out across nearly every gastrointestinal tumor type. In gastric cancer models, the natural compounds apigenin, deltonin, pectolinarigenin, and the coral-derived sinulariolide all induced apoptosis, autophagy, or cell cycle arrest by suppressing PI3K/AKT/mTOR signaling, with deltonin additionally sensitizing cells to cisplatin. The dual PI3K/mTOR inhibitor NVP-BEZ235 augmented the efficacy of fluorouracil in gastric cancer cells and enhanced chemotherapy and antiangiogenic responses in pancreatic cancer models. In pancreatic cancer stem cells, rottlerin triggered autophagy leading to apoptotic death through pathway inhibition. Everolimus, the mTORC1 inhibitor known as RAD001, inhibited tumor growth in hepatocellular carcinoma xenografts, while the novel inhibitor W922 prevented colorectal cancer growth through autophagy regulation. Dual targeting of the MAP kinase and PI3K/mTOR pathways showed synergistic effects in preclinical colorectal cancer models, and the p70S6K/AKT dual inhibitor DIACC3010 proved efficacious in gastric cancer models both alone and in combination with trastuzumab.

Translating this laboratory promise into clinical benefit has proven far harder. The phase III GRANITE-1 trial tested everolimus against placebo in previously treated advanced gastric cancer and failed to meet its survival endpoint, despite earlier phase II activity. A SWOG phase II study of the allosteric AKT inhibitor MK-2206 as second-line therapy for advanced gastric and gastroesophageal junction cancer likewise yielded disappointing results. In metastatic colorectal cancer, a phase II study of everolimus in patients previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens showed limited benefit. Everolimus in gemcitabine-refractory metastatic pancreatic cancer and temsirolimus combined with sorafenib in advanced hepatocellular carcinoma produced similarly modest outcomes. Phase II studies of the AKT inhibitor ipatasertib added to mFOLFOX6 in gastric cancer, and of copanlisib combined with gemcitabine and cisplatin in advanced biliary tract cancers, underscored both the interest in the strategy and the difficulty of demonstrating clear gains.

The review identifies toxicity as a principal culprit in these clinical setbacks, and the class effects are rooted in the pathway’s normal physiology. Because PI3K/AKT/mTOR signaling is central to glucose homeostasis, lipid metabolism, and cell survival in healthy tissues, its inhibition produces hyperglycemia, diarrhea, hepatotoxicity, neuropsychiatric effects, mucositis, skin rash, and metabolic complications. Meta-analyses of everolimus trials documented substantial rates of stomatitis, and studies of temsirolimus confirmed frequent rash and mucosal injury. Hyperglycemic complications on phase I trials of PI3K-AKT-mTOR inhibitors have been systematically characterized, and preclinical work suggests PI3K/AKT inhibitors can aggravate death receptor-mediated hepatocyte apoptosis and liver injury, a particular concern in patients with underlying liver disease. These toxicities constrain dosing, force interruptions, and erode the therapeutic window that the drugs need to exert meaningful antitumor effects.

The authors also highlight a second, equally fundamental barrier: the lack of molecular stratification. Early trials enrolled unselected patients, mixing tumors whose pathway activation was driven by PIK3CA mutation with those in which the pathway was activated downstream, upstream, or not at all. Without biomarkers to identify which tumors are genuinely addicted to the axis, inhibitors were tested in populations diluted with patients unlikely to respond, diluting signal and inviting failure. The reviewers argue that refined personalization, guided by genomic and epigenetic profiling of pathway alterations, is essential, and they point to the growing recognition of crosstalk between microRNAs and the pathway as a potential source of predictive biomarkers. They further contend that combination strategies, pairing pathway inhibitors with chemotherapy, antiangiogenic agents, MAPK inhibitors, autophagy blockers such as chloroquine, or trastuzumab in HER2-positive disease, represent the most credible route to overcoming the feedback loops and parallel survival pathways that allow tumors to evade single-agent blockade.

The review’s conclusions land at a moment of renewed interest in the pathway across oncology, with lessons learned in breast cancer, where PI3K inhibitors have achieved regulatory success, informing expectations for gastrointestinal disease. The authors, writing from the Student Research Committee and research institutes of Kashan University of Medical Sciences with collaborators in Tabriz, acknowledge that no datasets were generated or analyzed in the study and that it received no specific grant funding. Their synthesis ultimately delivers a dual verdict: the PI3K/AKT/mTOR axis is indisputably a central driver of gastrointestinal cancer progression, metastasis, and therapy resistance, and preclinical studies consistently show that its inhibition reduces tumor growth, induces cell death, and boosts chemosensitivity. Whether that promise finally reaches patients, they conclude, will depend on biomarker-driven trial designs, smarter combinations, and toxicity management strategies that respect the pathway’s indispensable role in healthy physiology as much as its corrupting influence in cancer.

Subject of Research: Targeting the PI3K/AKT/mTOR signaling pathway in gastrointestinal cancers

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

Article References: Kaikavoosnejad, F., Haddad Kashani, H., Dizaji Asl, K., Mazloumi, Z., Keyhani, A., Ashraf Moosavi, S. S., Verdi, M., & Rafat, A. (2026). Targeting the PI3K/AKT/mTOR pathway in gastrointestinal cancers: a comprehensive review of mechanisms, preclinical evidence, and clinical challenges. Medical Oncology, 43(10), Article 256. https://doi.org/10.1007/s12032-026-03374-8

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03374-8

Keywords: PI3K/AKT/mTOR pathway, gastrointestinal cancers, targeted therapy, colorectal cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, mTOR inhibitors, drug resistance, hyperglycemia, biomarkers, combination therapy