bims-pideca 2020-09-27 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2020–09–27
seven papers selected by
Ralitsa Radostinova Madsen, University College London

Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer.
Nutrient metabolism and cancer in the in vivo context: a metabolic game of give and take.
[New European approvals: Alpelisib for HRpos/HER2neg metastatic breast cancer with PIK3CA mutation].
Phosphoinositide lipids in primary cilia biology.
Mechanisms by which membrane and nuclear ER alpha inhibit adipogenesis in cells isolated from female mice.
Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations.
Mice Are Not Humans: The Case of p53.

Cancer Cell. 2020 Sep 14. pii: S1535-6108(20)30427-X. [Epub ahead of print]

Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer.

Susana Ros, Alan J Wright, Paula D'Santos, De-En Hu, Richard L Hesketh, Yaniv Lubling, Dimitra Georgopoulou, Giulia Lerda, Dominique-Laurent Couturier, Pedram Razavi, Rapahel Pelossof, Ankita S Batra, Elizabeth Mannion, David Y Lewis, Alistair Martin, Richard D Baird, Mafalda Oliveira, Leonora W de Boo, Sabine C Linn, Maurizio Scaltriti, Oscar M Rueda, Alejandra Bruna, Carlos Caldas, Kevin M Brindle.

  PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER+ breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized 13C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[18F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.

Keywords:  FDG-PET; FOXM1; MRI; PI3K alpha inhibition; biomarker; breast cancer; hexokinase 2; hyperpolarized [1-(13)C]pyruvate; lactate dehydrogenase; treatment response

DOI:  https://doi.org/10.1016/j.ccell.2020.08.016
EMBO Rep. 2020 Sep 23. e50635

Nutrient metabolism and cancer in the in vivo context: a metabolic game of give and take.

Patricia Altea-Manzano, Alejandro M Cuadros, Lindsay A Broadfield, Sarah-Maria Fendt.

  Nutrients are indispensable resources that provide the macromolecular building blocks and energy requirements for sustaining cell growth and survival. Cancer cells require several key nutrients to fulfill their changing metabolic needs as they progress through stages of development. Moreover, both cell-intrinsic and microenvironment-influenced factors determine nutrient dependencies throughout cancer progression-for which a comprehensive characterization remains incomplete. In addition to the widely studied role of genetic alterations driving cancer metabolism, nutrient use in cancer tissue may be affected by several factors including the following: (i) diet, the primary source of bodily nutrients which influences circulating metabolite levels; (ii) tissue of origin, which can influence the tumor's reliance on specific nutrients to support cell metabolism and growth; (iii) local microenvironment, which dictates the accessibility of nutrients to tumor cells; (iv) tumor heterogeneity, which promotes metabolic plasticity and adaptation to nutrient demands; and (v) functional demand, which intensifies metabolic reprogramming to fuel the phenotypic changes required for invasion, growth, or survival. Here, we discuss the influence of these factors on nutrient metabolism and dependence during various steps of tumor development and progression.

Keywords:  cancer metabolism; diet; microenvironment; nutrients; tumor heterogeneity

DOI:  https://doi.org/10.15252/embr.202050635
Bull Cancer. 2020 Sep 22. pii: S0007-4551(20)30350-7. [Epub ahead of print]

[New European approvals: Alpelisib for HRpos/HER2neg metastatic breast cancer with PIK3CA mutation].

Pauline Corbaux, Renaud Sabatier.



Keywords:  Cancer du sein RH+/HER2; HRpos/HER2neg breast cancer; Inhibiteur de PI3K; Mutation PIK3CA; PI3K inhibitor; PI3K/AKT/mTOR pathway; PIK3CA mutation; Voie PI3K/AKT/mTOR

DOI:  https://doi.org/10.1016/j.bulcan.2020.07.007
Biochem J. 2020 Sep 30. 477(18): 3541-3565

Phosphoinositide lipids in primary cilia biology.

Sarah E Conduit, Bart Vanhaesebroeck.

  Primary cilia are solitary signalling organelles projecting from the surface of most cell types. Although the ciliary membrane is continuous with the plasma membrane it exhibits a unique phospholipid composition, a feature essential for normal cilia formation and function. Recent studies have illustrated that distinct phosphoinositide lipid species localise to specific cilia subdomains, and have begun to build a 'phosphoinositide map' of the cilium. The abundance and localisation of phosphoinositides are tightly regulated by the opposing actions of lipid kinases and lipid phosphatases that have also been recently discovered at cilia. The critical role of phosphoinositides in cilia biology is highlighted by the devastating consequences of genetic defects in cilia-associated phosphoinositide regulatory enzymes leading to ciliopathy phenotypes in humans and experimental mouse and zebrafish models. Here we provide a general introduction to primary cilia and the roles phosphoinositides play in cilia biology. In addition to increasing our understanding of fundamental cilia biology, this rapidly expanding field may inform novel approaches to treat ciliopathy syndromes caused by deregulated phosphoinositide metabolism.

Keywords:  ciliopathy; phosphoinositides; primary cilia

DOI:  https://doi.org/10.1042/BCJ20200277
Endocrinology. 2020 Sep 25. pii: bqaa175. [Epub ahead of print]

Mechanisms by which membrane and nuclear ER alpha inhibit adipogenesis in cells isolated from female mice.

Amrita Ahluwalia, Neil Hoa, Lisheng Ge, Bruce Blumberg, Ellis R Levin.

  Mesenchymal stem cells can differentiate into mature chondrocytes, osteoblasts, and adipocytes. Excessive and dysfunctional visceral adipocytes increase upon menopause and importantly contribute to altered metabolism in post-menopausal women. We previously showed both plasma membrane and nuclear estrogen receptors alpha (ERα) with endogenous estrogen are required to suppress adipogenesis in-vivo. Here we determined mechanisms by which these liganded ER pools collaborate to inhibit the peroxisome proliferator-activated gamma (PPARγ) gene and subsequent progenitor differentiation. In 3T3-L1 pre-adipocytes and adipose-derived stem cells (ADSC), membrane ERα signaled through PI3K-AKT to enhance ERα nuclear localization, importantly at the PPARγ gene promoter. AKT also increased overall abundance and recruitment of co-repressors GATA3, β-catenin, and TCF4 to the PPARγ promoter. Membrane ERα signaling additionally enhanced wingless-integrated (Wnt)1 and 10b expression. The components of the repressor complex were required for estrogen to inhibit Rosiglitazone induced differentiation of ADSC and 3T3-L1 cells to mature adipocytes. These mechanisms whereby ER cellular pools collaborate to inhibit gene expression limit progenitor differentiation to mature adipocytes.

Keywords:  : Estrogen Receptor; Adipogenesis; Co-Repressors; Signal Transduction; Stem Cells

DOI:  https://doi.org/10.1210/endocr/bqaa175
Future Oncol. 2020 Sep 23.

Alpelisib in the treatment of metastatic HR+ breast cancer with PIK3CA mutations.

Athanasios Mavratzas, Frederik Marmé.

  Since the US FDA approval of everolimus/exemestane in July 2012, and of the first CDK 4/6 inhibitor, palbociclib, combined with endocrine treatment in February 2015, a third class of therapeutic compounds, the PI3K inhibitors, has been introduced to the arsenal of targeted therapies overcoming endocrine resistance in hormone receptor-positive metastatic breast cancer. Alpelisib (PIQRAY®) is the first of these novel agents yielding promising clinical results, giving an impetus to further development of tailored endocrine anticancer treatments. Herein, we review its pharmacodynamic and pharmacokinetic properties, safety and efficacy data, as well as Phase III SOLAR-1 trial, prompting FDA approval of alpelisib in hormone receptor-positive metastatic breast cancer harboring PIK3CA mutations. Furthermore, implications for clinical use and current research will also be discussed.

Keywords:  PI3K pathway; PIK3CA mutations; alpelisib; metastatic hormone receptor-positive breast cancer

DOI:  https://doi.org/10.2217/fon-2020-0464
Trends Cancer. 2020 Sep 17. pii: S2405-8033(20)30239-9. [Epub ahead of print]

Mice Are Not Humans: The Case of p53.

Martin Fischer.

  Mouse models represent powerful tools in cancer research that have influenced much of our understanding of tumor development and our current anticancer strategies. Yet, central signaling pathways differ considerably between mouse and human, including gene regulatory networks (GRNs) of the most important tumor suppressor p53 and its oncogenic sibling p63.

Keywords:  cancer research; evolution; gene regulatory networks; mouse models; p53; p63

DOI:  https://doi.org/10.1016/j.trecan.2020.08.007