Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

The fatty acid receptor CD36 promotes HCC progression through activating Src/PI3K/AKT axis-dependent aerobic glycolysis

“…Interestingly, CD36 overexpression not only increased the phosphorylation of Src but also activated its key downstream targets, namely PI3K and AKT. PI3K/AKT is an upstream regulator of mTOR, which is also crucial for the regulation of glycolysis by inducing glycolytic enzymes 40 , 41 . Thus, our results suggested that CD36 dramatically activates mTOR phosphorylation via Src/PI3K/AKT signal axis, resulting in enhanced glycolytic pathway, and ultimately promotes HCC growth and metastasis.…”

CDK4/6 Inhibition Reprograms Mitochondrial Metabolism in BRAFV600 Melanoma via a p53 Dependent Pathway

“…Notably, the available evidence supports a multifaceted and context-dependent role for CDK4/6 in metabolism [ 34 ]. A role for CDK4 in glycolysis has been described in mouse embryonic fibroblasts (MEFs), whereby CDK4 knockout impairs anaerobic glycolysis [ 17 ], whilst the CDK4/6 inhibitor palbociclib reduces glycolysis in triple-negative breast cancer [ 40 , 41 ] and mesothelioma [ 42 ]. Glucose metabolism also appears to underpin synergistic activities of palbociclib in combination with PI3K/mTOR inhibitors in triple-negative breast cancer [ 41 ].…”

Evaluation of tumour heterogeneity by 18F-fluoroestradiol PET as a predictive measure in breast cancer patients receiving palbociclib combined with endocrine treatment

“…Although ER expression is required for a response to palbociclib plus endocrine therapy, other pathways may also affect the efficacy of palbociclib, such as the androgen receptor (AR) signalling pathway [ 42 ]. A single 18 F-FES PET scan failed to show crosstalk with other pathways; therefore, it would be of interest in future studies to add multiple molecular imaging probes to improve the predicted response to palbociclib-based treatment, such as 18 F-fluoro-5α-dihydrotestosterone ( 18 F-FDHT)-PET for imaging AR [ 43 ] and 18 F-FDG PET for imaging the glycolytic metabolism tumour burden [ 44 ]. Finally, we were unable to obtain serial tumour biopsies to assess ER status, especially liver metastases (ER status cannot be reliably measured in liver metastases due to high background 18 F-FES avidity), thus limiting information on the accuracy of the 18 F-FES PET imaging of ER status.…”