bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2026–09–13
nine papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. Reconstructing signaling histories of single cells via perturbation screens and transfer learning.
  2. Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
  3. HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.
  4. Phenotypic manifestations and variant reclassification of germline PTEN variants: a nationwide Danish study.
  5. Inavolisib for PIK3CA-mutated advanced endometrial cancer: a multicentric, phase II, MITO END-4 trial.
  6. Isoform-Selective Targeting of Akt Through Covalent Allosteric Inhibition.
  7. KinaseDB: an integrated multi-omics platform for the human kinome with disease-specific target prioritization.
  8. Learning stochastic dynamics and cell-fate landscapes from single-cell snapshots via optimal transport.
  9. Understanding the distinct role of PI3K(p110α) in cancer and the heart to prevent chemotherapy-induced cardiotoxicity: mechanisms and therapeutic opportunities.
  1. Nat Methods. 2026 Sep 08.
    Reconstructing signaling histories of single cells via perturbation screens and transfer learning.
    Nicholas T Hutchins, Miram Meziane, Claire Lu, Maisam Mitalipova, David S Fischer, Pulin Li.
      Manipulating the signaling environment is an effective approach to alter cellular states for broad-ranging applications. Such manipulation requires knowing the signaling states and histories experienced by cells in vivo, for which high-throughput discovery methods are lacking. Here we present an integrated experimental-computational framework that learns transferable signaling response signatures from a high-throughput in vitro perturbation atlas and infers signaling activities and histories in in vivo cell types with high accuracy and temporal resolution. We generated a signaling perturbation atlas on human pluripotent stem cells and used it to train IRIS, a neural-network model. Applying IRIS to mouse embryo single-cell atlases, we uncovered global features of combinatorial signaling code usage, identified biologically meaningful heterogeneity and reconstructed signaling histories along diverse developmental lineages. This framework reveals that diverse cell types share conserved signaling response signatures, and provides a scalable solution for mapping complex signaling interactions in vivo to guide targeted interventions and enable cell fate engineering.
    DOI:  https://doi.org/10.1038/s41592-026-03213-8
  2. JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]
    Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.
    Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.
      Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.
    Keywords:  Endocrinology; Muscle biology; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.210523
  3. Sci Signal. 2026 Sep 08. 19(954): eaej6209
    HRAS promotes mutant NRAS-driven transformation with codon and allele specificity.
    Hyun Lee, Jacob M Hughes, Joseph P LaMorte, Bridget A Finniff, Picabo Binette, Sarasi K Gunasekara, Ariana Covas, Vanessa E Wall, Dominic Esposito, Matthew D Wilkerson, Marielle E Yohe, Robert L Kortum.
      Wild-type RAS family members determine the signaling and therapeutic response in cancers driven by mutant HRAS and KRAS because they activate alternate RAS effector pathways. Here, we found that the requirement for wild-type RAS to support mutant NRAS-driven transformation correlated with codon-specific differences in GTP hydrolysis. NRAS with mutations at either Gly12 (G12X) or Gly13 (G13X), which retained the GDP-GTP cycling function, had modest autonomous transforming potential. In contrast, NRAS with GTP-locking mutations at Gln61 (Q61X mutants) was uncoupled from receptor tyrosine kinase (RTK) input, rendering wild-type RAS an obligate partner for RTK-stimulated signaling and oncogenesis. In RASless cells expressing mutant NRAS, reintroduction of wild-type HRAS was sufficient to restore signaling and transformation. Global dependency mapping in human cancer cells revealed functional partitioning, wherein mutant NRAS promoted MAPK signaling and wild-type HRAS promoted PI3K-AKT survival signaling. Consequently, allele-specific or pan-RAS(ON) inhibitors synergized with inhibitors of proximal RTK signaling or of wild-type HRAS or KRAS to overcome this signaling plasticity. Pan-RAS(ON) and HRAS inhibition was synergistic for all NRAS mutants tested, with Q61X mutants showing greater sensitivity. These findings define the signaling partnership between mutant NRAS and wild-type HRAS as a targetable vulnerability and provide a biochemical blueprint for dual RAS inhibition in NRAS-mutated malignancies.
    DOI:  https://doi.org/10.1126/scisignal.aej6209
  4. J Med Genet. 2026 Sep 09. pii: jmg-2026-111772. [Epub ahead of print]
    Phenotypic manifestations and variant reclassification of germline PTEN variants: a nationwide Danish study.
    Annette Lyngholm Sandsdalen, Anne Marie Jelsig, Birgitte Bertelsen, Zuzana Lohse, Annabeth Hogh Petersen, Maja Smerdel, Inge Sokilde Pedersen, Malene Lundsgaard, Lise Lotte Christensen, Charlotte Lautrup, Susanne Eriksen Boonen, Mads Thomassen, Karin A W Wadt, Thomas van Overeem Hansen.
       BACKGROUND: Classification of heterozygous germline PTEN variants in patients with, or suspected of having, PTEN hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveillance.
    METHODS: We identified all patients with a PTEN variant previously classified as a variant of uncertain significance (VUS), likely pathogenic (LP) or pathogenic (P), collected clinical data and reclassified all variants using the latest PTEN gene-specific American College of Medical Genetics (ACMG) guidelines. Moreover, genotype-phenotype correlations were assessed.
    RESULTS: 167 patients from 112 families were enrolled. Eighty-seven unique PTEN variants were identified, including 20 novel variants. After applying the PTEN gene-specific ACMG guidelines, 32 variants (36.8%) were reclassified, resulting in 60 PTEN variants classified as LP/P (69.0%), 18 variants classified as VUS (20.7%), while 9 variants were classified as LB/B (10.3%). Genotype-phenotype correlation was performed among 104 patients with LP/P variants: 51 cancer cases were recorded in 41 patients and a distinct PHTS phenotype was observed in 25% of patients, with macrocephaly being present in 99% of patients with a known head circumference. Twenty-three patients had neurodevelopmental delay and/or autism, and we observed an increased prevalence of missense variants in these patients.
    CONCLUSION: We identified 87 different PTEN variants, and application of PTEN gene-specific ACMG guidelines led to reclassification of 32 variants (36.8%), underscoring the importance of regular variant reassessment using the most recent gene-specific guidelines, ensuring optimal patient management and surveillance.
    Keywords:  Genetic Predisposition to Disease; Genetic Variation; Genetics; Genotype; Phenotype
    DOI:  https://doi.org/10.1136/jmg-2026-111772
  5. Int J Gynecol Cancer. 2026 Aug 09. pii: S1048-891X(26)00488-3. [Epub ahead of print] 104957
    Inavolisib for PIK3CA-mutated advanced endometrial cancer: a multicentric, phase II, MITO END-4 trial.
    Anna Passarelli, Michele Bartoletti, Alberto Farolfi, Maria Lucia Iacovino, Francesco Perrone, Clorinda Schettino, Laura Arenare, Marcella Montico, Gustavo Baldassarre, Daniela Califano, Carmela Pisano, Valeria Andretta, Grazia Artioli, Alice Bergamini, Roberto Bianco, Alessandra Bologna, Domenica Lorusso, Anna Fagotti, Marica Gentile, Stefania Napolitano, Elena Poletto, Antonella Savarese, Giuseppa Scandurra, Giorgio Valabrega, Claudio Zamagni, Yvonne G Lin, Layal Maatouk, Sandro Pignata.
       BACKGROUND: The phosphatase and tensin homolog-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway is frequently altered in gynecological tumors, notably in endometrial cancer where PIK3CA mutations are found in nearly half of patients. Despite this, evidence of clinical activity of PI3K inhibitors in endometrial cancer is poor and limited. Alpelisib, an oral PI3K alpha-selective inhibitor, showed encouraging preliminary activity in advanced gynecological tumors harboring PIK3CA alterations. Inavolisib is a highly potent and selective PI3K inhibitor.
    PRIMARY OBJECTIVE(S): The MITO END-4 trial aims to assess the efficacy and safety of inavolisib in patients with endometrial cancer who have received platinum-based chemotherapy and immunotherapy. The primary objective is to determine the anti-tumor activity (assessed by objective response rate) of inavolisib in patients with advanced endometrial cancer with PIK3CA mutated tumors.
    STUDY HYPOTHESIS: The study tests the hypothesis that inavolisib has superior anti-tumor activity compared to historically available standard therapies in previously treated patients with advanced endometrial cancer harboring a PIK3CA mutation.
    TRIAL DESIGN: This is a phase II, single-arm, multicenter trial in which advanced endometrial cancer patients whose tumors harbor a pathogenic PIK3CA mutation will receive inavolisib.
    MAJOR INCLUSION/EXCLUSION CRITERIA: Patients aged 18 years and older with documented evidence of PIK3CA mutated advanced endometrial cancer (endometrioid, serous, clear cell, carcinosarcoma or mixed histology) will be enrolled. Patients have previously received at least 1 platinum-based chemotherapy in any setting (adjuvant or advanced) with or without immune checkpoint inhibitor, alone or in combination. Not more than 4 lines of therapy are allowed. Key exclusion criteria include uterine sarcoma and prior treatment with any PI3K, AKT, or mechanistic target of rapamycin (mTOR) inhibitor.
    PRIMARY ENDPOINT(S): Objective response rate defined as a complete response or partial response by the Investigator using RECIST v1.1 criteria over the whole treatment period.
    SAMPLE SIZE: 48 patients.
    ESTIMATED DATES FOR COMPLETING ACCRUAL: May 2028.
    TRIAL REGISTRATION: MITO END-4; EU-CT NUMBER: 2025-522981-61-00; NCT07522697.
    Keywords:  Endometrial cancer; Inavolisib; MITO END-4; PIK3CA mutation; The Cancer Genome Atlas
    DOI:  https://doi.org/10.1016/j.ijgc.2026.104957
  6. Angew Chem Int Ed Engl. 2026 Sep 07. e3567206
    Isoform-Selective Targeting of Akt Through Covalent Allosteric Inhibition.
    Giovanni Danilo D'Angelo, Kosmas Alexandros Pervanidis, Ioannis Athanasiadis, Vladimir Lukianchikov, Andrea Scrima, Laura Depta, Sara Stier, Matthias P Müller, Henner F Farin, Lena Quambusch, Daniel Rauh.
      The Akt family of serine/threonine kinases plays a crucial role in various cellular processes, including proliferation, survival, and metabolism. Three Akt isoforms (Akt1, Akt2, and Akt3) have distinct physiological roles, and while individual isoform dysregulation is disease-linked, unselective Akt inhibition leads to side effects. Here, we report the development of selective covalent-allosteric Akt inhibitors (CAAIs) targeting Akt2 and Akt3 while sparing Akt1. Guided by protein x-ray crystallography and molecular modeling, key structural differences within the allosteric pockets of the isoforms were identified and exploited in a structure-based design strategy. By stabilizing the inactive kinase conformation, CAAIs overcome the intrinsic selectivity limitations of ATP-competitive inhibitors. After biological characterization, the pyrazole-containing inhibitors emerged as the most potent and selective Akt2 inhibitors, while inhibitors with pyridines as an isoform-selective element were predominantly targeting Akt3 selectively. Importantly, these new inhibitors were also evaluated in patient-derived colorectal cancer organoids. Co-crystal structures of inhibitors bound to an engineered construct mimicking the Akt2 allosteric pocket elucidated the molecular basis of isoform selectivity, guiding further optimization. This work not only establishes a framework for the development of isoform-selective therapeutics but also highlights the potential for unraveling isoform-specific functions in signaling pathways relevant to cancer biology.
    Keywords:  Akt isoform‐selectivity; allosteric modulation; covalent inhibition; structure‐based‐drug‐design
    DOI:  https://doi.org/10.1002/anie.3567206
  7. Nucleic Acids Res. 2026 Sep 11. pii: gkag881. [Epub ahead of print]
    KinaseDB: an integrated multi-omics platform for the human kinome with disease-specific target prioritization.
    Sadiyah Afroz, Idhant Arora, Harsh Hingorani, Harsh Rawat, Madhav Kansil, Arjun Ray.
      Protein kinases govern cellular signalling and disease progression and represent major therapeutic targets, yet comprehensive characterization across the human kinome remains hindered by data fragmentation across specialized resources. Here, we present KinaseDB (https://kinasedb.raylab.iiitd.edu.in), a freely accessible web resource integrating curated multi-omics data for 559 human protein kinases from 11 core resources, supplemented by specialized functional-site annotation datasets. KinaseDB provides structural annotations derived from experimental structures, AlphaFold models, and homology modelling; kinome-wide druggability assessments using fpocket; a provenance-aware kinase-substrate dataset comprising site-resolved and relationship-only interactions; cellular-resolution snRNA-seq expression profiles across 625 tissue-cell-type combinations; disease associations with drug-tractability annotations; and population-scale genetic variation data within a single platform. To enable target prioritization, KinaseDB introduces a kinase prioritization score (KPS) that integrates seven complementary evidence components across 69 disease contexts, comprising 38 571 kinase-disease pairs. The KPS discriminated FDA-approved kinase-inhibitor targets from IDG dark kinases with an AUROC of 0.773 (95% bootstrap CI: 0.615-0.908) and an AUPRC of 0.875 (95% bootstrap CI: 0.747-0.968). Rankings were broadly robust to the tested weight perturbations (Spearman $\rho = 0.84$-0.98 across five alternative weighting schemes). All data, bulk downloads, and a documented REST API are publicly available through KinaseDB.
    DOI:  https://doi.org/10.1093/nar/gkag881
  8. Sci Adv. 2026 Sep 11. 12(37): eaeb4205
    Learning stochastic dynamics and cell-fate landscapes from single-cell snapshots via optimal transport.
    Juntan Liu, Peijie Zhou, Qing Nie, Chunhe Li.
      The temporal dynamics and stochasticity of gene expression are critical to cell fate decisions, yet integrating snapshot omics data across multiple time points remains a major challenge. Here, we introduce DiffusionOT, a dynamic machine learning framework that infers cellular trajectories from multi-time point single-cell transcriptomics by incorporating stochastic effects. DiffusionOT transforms stochastic differential equations into ordinary differential equations, using optimal transport and neural networks to solve a high-dimensional landscape model. Through an unsupervised learning of the stochastic force in the data, DiffusionOT allows robust inference of the underlying stochastic dynamics of cell-state transitions. The framework includes a stochastic trajectory analysis module for lineage tracing and a gene perturbation module for in silico knockout and overexpression experiments. Benchmarks on simulated and four real-world datasets, including a spatial Stereo-seq dataset, demonstrate DiffusionOT's accuracy and efficiency in inferring state-transition velocities, cellular trajectories, population growth, gene regulatory networks, and cell-fate landscape.
    DOI:  https://doi.org/10.1126/sciadv.aeb4205
  9. Front Cardiovasc Med. 2026 ;13 1891148
    Understanding the distinct role of PI3K(p110α) in cancer and the heart to prevent chemotherapy-induced cardiotoxicity: mechanisms and therapeutic opportunities.
    Teleah G Belkin, Yow Keat Tham, Amanda J Edgley, Julie R McMullen.
      The development of new cancer therapies with greater efficacy has reduced mortality for many cancers, as well as improving survivorship. However, for some cancer treatments, this has uncovered unintended cardiotoxicity during or after treatment, and cardiovascular disease has emerged as a leading cause of mortality in some cancer survivors. This may occur because many of the same growth factor signaling pathways that lead to tumor growth are also critical for maintaining normal heart function. A class IA phosphoinositide 3-kinase, PI3K(p110α), is a critical regulator of normal heart biology, function and exercise-induced cardiac protection, but is also mutated/increased in some cancer types. In this review, we discuss the dual role of PI3K(p110α) signaling in cancer and the heart. The paradox being, that inhibiting PI3K(p110α) in a setting of some cancer types would be beneficial for halting/slowing tumor progression but could also damage heart muscle cells. Exercise and PI3K(p110α) has beneficial effects on heart function via cardiac excitation and contraction, mitochondrial adaptations, cellular stress responses to promote survival, preventing cell death and cardiac fibrosis. We contrast this to the chemotherapy, doxorubicin, which is crucial for the treatment of many cancers but negatively impacts many of the beneficial effects of exercise and PI3K(p110α). Doxorubicin's clinical efficacy is limited by dose-dependent cardiotoxicity including cardiomyopathy, atrial fibrillation, and heart failure. A summary of reported cardiovascular effects in clinical trials using PI3K inhibitors is also provided. Finally, we discuss some of the current and emerging approaches to mitigate cancer therapy-induced cardiotoxicity including pharmacological interventions, gene therapy and dietary approaches based on preclinical studies. Advances in the field are likely to come from continued refinement of cardiotoxicity models, the investigation of targeting molecular pathways and targets with relevant primary endpoints for both cancer and heart function, and collaborative research with discovery/preclinical scientists and clinicians.
    Keywords:  PI3K; cancer; cardiotoxicity; doxorubicin; heart failure
    DOI:  https://doi.org/10.3389/fcvm.2026.1891148
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