ReviewMolecular cancer therapeutics2014
Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance.
Review in Molecular cancer therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 194 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
194 citing papers in PubMed, 2 syntheses or guidelines pooled it, 302 citations in OpenAlex.
- Fasting-mimicking diets as a strategy to reprogram tumor metabolism: a systematic review.European journal of nutrition · 2026Pooled it
- The prognostic value of PI3K mutational status in breast cancer: A meta-analysis.Journal of cellular biochemistry · 2018Pooled it
- Randomized Phase II Trial of Sapanisertib ± TAK-117 vs. Everolimus in Patients With Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy.The oncologist · 2022Trial
- Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Trial
- Pdcd4-Rictor interaction suppresses mTORC2-PFKFB3 axis and tumorigenesis in NSCLC.Neoplasia (New York, N.Y.) · 2026Article
- PTBP1-Mediated Alternative Splicing of DNAJB6 Promotes Everolimus Resistance in Clear Cell Renal Cell Carcinoma via EIF4B/PKIB/AKT/mTOR Positive Feedback Loop.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Quantitative interactome mapping of skeletal muscle insulin resistance.Molecular systems biology · 2026Article
- Dual Targeting of FGFR4 and PI3K-mTOR Suppresses Tumor-Associated Phenotypes in Pancreatic Ductal Adenocarcinoma.International journal of molecular sciences · 2026Article
- mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia.Leukemia · 2026Article
- Ginsenoside RgJournal of natural medicines · 2026Article
- Rewiring mTOR signaling in Alzheimer's disease: emerging mTOR modulators beyond oncology.Bioscience reports · 2026Review
- Repurposing niclosamide to mitigate inflammaging: a review of multi-target mechanisms in cellular senescence and age-related decline.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- Article
- Vitexin inhibits renal cell carcinoma progression by targeting Galectin-1-mediated glycolytic metabolism.Molecular biology reports · 2026Article
- Electrical gastrodin-polyurethane spiral conduits with micro/nano-structure for accelerating peripheral nerve regeneration.Bioactive materials · 2026Article
- Pdcd4-Rictor Interaction Suppresses PFKFB3 to inhibit Tumorigenesis.Research square · 2026Article
- Article
- Integrative In Silico mRNA-miRNA Profiling of mTOR Pathway Dysregulation in High-Grade Serous Ovarian Carcinoma.Cancers · 2026Article
- Sex Bias in IL-10 Production by Type I Regulatory T Cells Regulated by PI3K/mTOR Signaling.Neurology(R) neuroimmunology & neuroinflammation · 2026Article
134 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
The development of drug resistance by cancer cells is recognized as a major cause for drug failure and disease progression. The PI3K/AKT/mTOR pathway is aberrantly stimulated in many cancer cells and thus it has emerged as a target for therapy. However, mTORC1 and S6K also mediate potent negative feedback loops that attenuate signaling via insulin/insulin growth factor receptor and other tyrosine kinase receptors. Suppression of these feedback loops causes overactivation of upstream pathways, including PI3K, AKT, and ERK that potentially oppose the antiproliferative effects of mTOR inhibitors and lead to drug resistance. A corollary of this concept is that release of negative feedback loops and consequent compensatory overactivation of promitogenic pathways in response to signal inhibitors can circumvent the mitogenic block imposed by targeting only one pathway. Consequently, the elucidation of the negative feedback loops that regulate the outputs of signaling networks has emerged as an area of fundamental importance for the rational design of effective anticancer combinations of inhibitors. Here, we review pathways that undergo compensatory overactivation in response to inhibitors that suppress feedback inhibition of upstream signaling and underscore the importance of unintended pathway activation in the development of drug resistance to clinically relevant inhibitors of mTOR, AKT, PI3K, or PI3K/mTOR.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.