Ho Woon Fei

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Antonino Glaviano1, Aaron S. C. Foo2, Hiu Y. Lam3,4, Kenneth C. H. Yap3,4, William Jacot5, Robert H. Jones6,
Huiyan Eng2,3, Madhumathy G. Nair7, Pooyan Makvandi8, Birgit Geoerger9, Matthew H. Kulke10,
Richard D. Baird11, Jyothi S. Prabhu7, Daniela Carbone1, Camilla Pecoraro1, Daniel B. L. Teh12, Gautam Sethi2,3,
Vincenzo Cavalieri1, Kevin H. Lin13, Nathalie R. Javidi‑Sharifi13, Eneda Toska14, Matthew S. Davids13,
Jennifer R. Brown13, Patrizia Diana1, Justin Stebbing15, David A. Fruman16 and Alan P. Kumar2,3*

Abstract

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes
cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis
is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction
can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human
cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such
as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance
and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer,
and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic
agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance
to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

Thach Tuan Pham, Anh Hong Le, Cong Phi Dang, Suet Yen Chong, Dang Vinh Do, Boya Peng,

Migara Kavishka Jayasinghe, Hong Boon Ong, Dong Van Hoang, Roma Anne Louise, Yuin-Han Loh,

HanWei Hou, Jiong-WeiWang, Minh TN Le

Abstract

Extracellular vesicles (EVs) can be produced from red blood cells (RBCs) on a large
scale and used to deliver therapeutic payloads efficiently. However, not much is
known about the native biological properties of RBCEVs. Here, we demonstrate that
RBCEVs are primarily taken up by macrophages and monocytes. This uptake is an
active process, mediated mainly by endocytosis. Incubation of CD14+ monocytes
with RBCEVs induces their differentiation into macrophages with an Mheme-like
phenotype, characterized by upregulation of heme oxygenase-1 (HO-1) and the ATPbinding
cassette transporter ABCG1. Moreover, macrophages that take up RBCEVs
exhibit a reduction in surface CD86 and decreased secretion of TNF-α under inflammatory
stimulation. The upregulation of HO-1 is attributed to heme derived from
haemoglobin in RBCEVs. Heme is released from internalized RBCEVs in late endosomes
and lysosomes via the heme transporter, HRG1. Consequently, RBCEVs
exhibit the ability to attenuate foamcell formation fromoxidized low-density lipoproteins
(oxLDL)-treated macrophages in vitro and reduce atherosclerotic lesions in
ApoE knockout mice on a high-fat diet. In summary, our study reveals the uptake
mechanism of RBCEVs and their delivery of heme to macrophages, suggesting the
potential application of RBCEVs in the treatment of atherosclerosis.

Fang Ji, PhD, Yuek Ling Chai, PhD, Siwei Liu, PhD, Cheuk Ni Kan, MSc, Marcus Ong, BSc,
Arthur Mark Richards, MD, Boon Yeow Tan, MMed, Narayanaswamy Venketasubramanian, FRCP,
Ofer Pasternak, PhD, Christopher Chen, MD, Mitchell K.P. Lai, PhD,* and Juan Helen Zhou, PhD*

Abstract

Background and Objectives: There is an increasing awareness of the “Heart-Brain Connection,” whereby cardiovascular function is connected with cognition. Diffusion-MRI studies reported higher brain free water (FW) was associated with cerebrovascular disease (CeVD) and cognitive impairment. In this study, we investigated whether higher brain FW was related to blood cardiovascular biomarkers and whether FW mediated the associations between blood biomarkers and cognition.

Methods: Participants recruited from 2 Singapore memory clinics between 2010 and 2015 underwent collection of blood samples and neuroimaging at baseline and longitudinal neuropsychological assessments up to 5 years. We examined the associations of blood cardiovascular biomarkers (high-sensitivity cardiac troponin-T [hs-cTnT], N-terminal pro-hormone B-type natriuretic peptide [NT-proBNP], and growth/differentiation factor 15 [GDF-15]) with brain white matter (WM) and cortical gray matter (GM) FWderived from diffusion MRI using whole brain voxel-wise general linear regression. We then assessed the relationships among baseline blood biomarkers, brain FW, and cognitive decline using path models.

Results: A total of 308 older adults (76 with no cognitive impairment, 134 with cognitive impairment no dementia, and 98 with Alzheimer disease dementia and vascular dementia; mean [SD] age: 72.1 [8.3]) were included. We found that blood cardiovascular biomarkers were associated with higher FW in widespreadWMregions and in specific GM networks including the default mode, executive control, and somatomotor networks at baseline (p < 0.01, family-wise error corrected). Baseline FW in widespread WM and network-specific GM fully mediated the associations of blood biomarkers with longitudinal cognitive decline over 5 years. Specifically, in GM, higher FW in the default mode network mediated the relationship with memory decline (hs-cTnT: β = −0.115, SE = 0.034, p = 0.001; NT-proBNP: β = −0.154, SE = 0.046, p = 0.001; GDF-15: β = −0.073, SE = 0.027, p = 0.006); by contrast, higher FW in the executive control network was responsible for executive function decline (hs-cTnT: β = −0.126, SE = 0.039, p = 0.001; NT-proBNP: β = −0.110, SE = 0.038, p = 0.004; GDF-15: β = −0.117, SE = 0.035, p = 0.001). Similar full mediation effects of brain FW were also identified for baseline cognition.

Discussion: Results suggested a role of brain FW in linking cardiovascular dysfunction to cognitive decline. These findings provide new evidence for brain-heart interactions, paving the way for prediction and monitoring of domain-specific cognitive trajectory.