Impairing energy metabolism in solid tumors through agents targeting oncogenic signaling pathways

Cell metabolic reprogramming is one of the main hallmarks of cancer and many oncogenic pathways that drive the cancer-promoting signals also drive the altered metabolism. This review focuses on recent data on the use of oncogene-targeting agents as potential modulators of deregulated metabolism in different solid cancers. Many drugs, originally designed to inhibit a specific target, then have turned out to have different effects involving also cell metabolism, which may contribute to the mechanisms underlying the growth inhibitory activity of these drugs. Metabolic reprogramming may also represent a way by which cancer cells escape from the selective pressure of targeted drugs and become resistant. Here we discuss how targeting metabolism could emerge as a new effective strategy to overcome such resistance. Finally, accumulating evidence indicates that cancer metabolic rewiring may have profound effects on tumor-infiltrating immune cells. Modulating cancer metabolic pathways through oncogene-targeting agents may not only restore more favorable conditions for proper lymphocytes activation, but also increase the persistence of memory T cells, thereby improving the efficacy of immune-surveillance

Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).CONCLUSIONS:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active

Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.USAMRMC {[}BC022276]; Intramural RECDA Award; Italian Association for Cancer Research (AIRC); MIUR-PRIN; Italian MIUR-FIRB Accordi di Programma; Italian ``Ministero dell'Istruzione, dell'Universita e della Ricerca (Ministry for Education, Universities and Research) - FIRB-MERIT {[}RBNE08YYBM]; Italian Ministry of Economy and Finance; Italian Ministry of Health, Ricerca Finalizzata Stemness; MIUR FIRB {[}RBAP11ZJFA\_001]; CRO; Italian Association for Cancer Research, (AIRC) (RM PI); Italian Association for Cancer Research, (AIRC) {[}MCO10016]; Italian Ministry of Health; Regione Friuli Venezia-Giuli

Hypertonic Stress and Amino Acid Deprivation Both Increase Expression of mRNA for Amino Acid Transport System A

Amino acid transport system A (SNAT2) in Chinese hamster ovary (CHO-K1) cells was stimulated when the cells were depleted of amino acids or subjected to hypertonic stress. Each of these stresses also caused increases in the abundance of SNAT2 mRNA in these cells. Similar results were obtained with Madin-Darby canine kidney (MDCK) cells, porcine pulmonary artery endothelial cells and human WI-38 fibroblasts. We conclude that the cellular signal transduction pathways for hypertonic stress and amino acid starvation must converge at or before transcription of the message for SNAT2

Dual inhibition of CDK4/6 and PI3K/AKT/mTOR signaling impairs energy metabolism in MPM cancer cells

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

Afatinib therapy in case of EGFR G724S emergence as resistance mechanism to osimertinib

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) used both as the first-line treatment of EGFR-mutated non-small cell lung cancer patients and in second-line after T790M-positive disease progression to first- or second-generation TKIs. Unfortunately, patients unavoidably experience disease progression to osimertinib and the current research is focused on resistance mechanisms and the relative therapeutic strategy. We report the case of a patient with advanced EGFR-mutated (exon 19 deletion and T790M-positive) non-small cell lung cancer who developed disease progression to osimertinib characterized by the loss of T790M concurrently with the emergence of G724S EGFR mutation, which was tackled by subsequent afatinib treatment. Next-generation sequencing molecular study of rebiopsy at time of progression to osimertinib revealed the persistence of EGFR exon 19 deletion, loss of T790M with a new G724S EGFR mutation; other concomitant mechanisms were excluded. Retrospective analysis of cell-free DNA revealed the emergence of G724S EGFR mutation four months before the radiologically-proven disease progression. The patient, after chemotherapy, was treated with afatinib with clinical and radiological benefit. Our case report contributes to increase the knowledge on acquired resistance mechanisms to osimertinib treatment, and it shows, for the first time, the efficacy of afatinib in the case of T790M loss and emergence of G724S EGFR mutation. Anti-Cancer Drugs 32: 758-762 Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

Advanced hepatocarcinoma (HCC) is an aggressive malignancy with poor prognosis and limited treatment options. Alterations of the cyclin D-CDK4/6-Rb pathway occur frequently in HCC, providing the rationale for its targeting at least in a molecular subset of HCC. In a panel of HCC cell lines, we investigated whether the CDK4/6 inhibitor palbociclib might improve the efficacy of regorafenib, a powerful multi-kinase inhibitor approved as second-line treatment for advanced HCC after sorafenib failure and currently under clinical investigation as first-line therapy in combination with immunotherapy. In Rb-proficient cells, the simultaneous drug combination, but not the sequential schedules, inhibited cell proliferation, either in short or in long-term experiments, and induced cell death more strongly than individual treatments. Moreover, the combination significantly reduced spheroid cell growth and inhibited cell migration/invasion. The superior efficacy of palbociclib plus regorafenib emerged also under hypoxia and was associated with a significant down-regulation of CDK4/6-Rb-myc and mTORC1/p70S6K signaling. Moreover, regorafenib suppressed palbociclib-induced expression of cyclin D1 contributing to the cytotoxic effects of the combination. Besides these inhibitory effects on cell viability/proliferation, palbociclib and regorafenib reduced glucose uptake, although this effect was dependent on the cell model and on the oxygen availability (normoxia or hypoxia). Palbociclib and regorafenib combination impaired glucose uptake and utilization, down-regulating basal and hypoxia-induced expression of HIF-1α, HIF-2α, GLUT-1, and MCT4 proteins as well as the activity/expression of glycolytic enzymes (HK2, PFKP, aldolase A, PKM2). In addition, regorafenib alone reduced mitochondrial respiration. The combined treatment impaired glucose metabolism and respiration without enhancing the effects of the single agents. Our findings provide pre-clinical evidence for the effectiveness of palbociclib and regorafenib combination in HCC cell models