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Significance: Cancer cells exhibit altered metabolic pathways to keep up with biosynthetic and reduction-oxidation needs during tumor proliferation and metastasis. The common induction of metabolic pathways during cancer progression, regardless of cancer histio- or genotype, makes cancer metabolism an attractive target for therapeutic exploitation. Recent Advances: Emerging data suggest that these altered pathways may even result in resistance to anticancer therapies. Identifying specific metabolic dependencies that are unique to cancer cells has proved challenging in this field, limiting the therapeutic window for many candidate drug approaches. Critical Issues: Cancer cells display significant metabolic flexibility in nutrient-limited environments, hampering the longevity of suppressing cancer metabolism through any singular approach. Combinatorial "synthetic lethal" approaches may have a better chance for success and promising strategies are reviewed here. The dynamism of the immune system adds a level of complexity, as various immune populations in the tumor microenvironment often share metabolic pathways with cancer, with successive alterations during immune activation and quiescence. Decoding the reprogramming of metabolic pathways within cancer cells and stem cells, as well as examining metabolic symbiosis between components of the tumor microenvironment, would be essential to further meaningful drug development within the tumor's metabolic ecosystem. Future Directions: In this article, we examine evidence for the therapeutic potential of targeting metabolic alterations in cancer, and we discuss the drawbacks and successes that have stimulated this field.

There is mounting evidence of oxidative phosphorylation (OXPHOS) dependency in cancers resistant to tyrosine kinase inhibitors (TKI), but the cause of this metabolic switch remains elusive. Mitochondria-bound MDM2 (mtMDM2), the fraction of MDM2 oncoprotein which is actively imported into the mitochondria, has been found to dysregulate electron transport chain (ETC) complex I function and OXPHOS. AKT is known to be a regulator of MDM2 protein stability. Given that AKT phosphorylation is commonly detected in oncogene-addicted tumours, we investigated the role of mtMDM2 and AKT in promoting TKI resistance through reprogrammed cellular metabolism. EGFR+ NSCLC [HCC827 and HCC827-GR (gefitinib-resistant)] and BRAF+ melanoma [A375 and A375-VR (vemurafenib-resistant)] cells were established via repetitive pulsed strategy. Translocation of MDM2 was examined through subcellular fractionation and Western Blotting. To investigate the role of MDM2 in mediating OXPHOS, genetic knockdown of MDM2 was performed via siRNA followed by measurement of oxygen consumption rate (Seahorse Analyzer); mRNA expression of mtDNA-encoded ETC subunits by real-time PCR (qPCR). ChIP-qPCR analysis was performed to examine the binding affinity of MDM2 and TFAM (mitochondrial transcription factor A) to mitochondrial DNA (mtDNA). Mitochondrial translocation of MDM2 was predominant in TKI-sensitive cells; MDM2 silencing upregulated OXPHOS and induced mRNA expression of mtDNA-encoded ETC complex I subunits, suggesting that mtMDM2 inhibits OXPHOS. ChIP analysis revealed competitive binding of MDM2 and TFAM at the LSP region of mtDNA. Conversely, MDM2 was primarily localized the cytoplasm in TKI-resistant cells and was associated with increased OXPHOS in TKI-resistant cells. Mechanistically, both pAKT and pMDM2 (Ser166/Ser186) were higher in TKI-resistant cells. Collectively, we describe a novel observation that OXPHOS upregulation underpinning TKI resistance in cancer cells could be mediated by AKT upregulation and MDM2 localisation. Citation Format: Jie Qing Eu, Li Ren Kong, Jayshree Hirpara, Boon Cher Goh, Andrea LA Wong, Shazib Pervaiz. MDM2 mitochondrial translocation mediates metabolic reprogramming towards OXPHOS in TKI-resistant oncogene-addicted cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5807.

Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

Signal transduction activator of transcription (STAT) 3 is a member of the STAT protein family which transduces intracellular and extracellular signals to the nucleus, controlling the expression of...

The ability to selectively eradicate oncogene-addicted tumors while reducing systemic toxicity has endeared targeted therapies as a treatment strategy. Nevertheless, development of acquired resistance limits the benefits and durability of such a regime. Here we report evidence of enhanced reliance on mitochondrial oxidative phosphorylation (OXPHOS) in oncogene-addicted cancers manifesting acquired resistance to targeted therapies. To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB). Of note, a priori treatment with OPB restored sensitivity to targeted therapies. Furthermore, cancer cells exhibiting stemness markers also showed selective reliance on OXPHOS and enhanced sensitivity to OPB. Importantly, in a subset of patients who developed secondary resistance to EGFR tyrosine kinase inhibitor (TKI), OPB treatment resulted in decrease in metabolic activity and reduction in tumor size. Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting. Keywords: Metabolic reprogramming, OXPHOS, Oncogene-addiction, STAT3

There is evidence to implicate reactive oxygen species (ROS) in tumorigenesis and its progression. This has been associated with the interplay between ROS and oncoproteins, resulting in enhanced cellular proliferation and survival. Recent Advances: To date, studies have investigated specific contributions of the crosstalk between ROS and signaling networks in cancer initiation and progression. These investigations have challenged the established dogma of ROS as agents of cell death by demonstrating a secondary function that fuels cell proliferation and survival. Studies have thus identified (onco)proteins (Bcl-2, STAT3/5, RAS, Rac1, and Myc) in manipulating ROS level as well as exploiting an altered redox environment to create a milieu conducive for cancer formation and progression.Despite these advances, drug resistance and its association with an altered redox metabolism continue to pose a challenge at the mechanistic and clinical levels. Therefore, identifying specific signatures, altered protein expressions, and modifications as well as protein-protein interplay/function could not only enhance our understanding of the redox networks during cancer initiation and progression but will also provide novel targets for designing specific therapeutic strategies.Not only a heightened realization is required to unravel various gene/protein networks associated with cancer formation and progression, particularly from the redox standpoint, but there is also a need for developing more sensitive tools for assessing cancer redox metabolism in clinical settings. This review attempts to summarize our current knowledge of the crosstalk between oncoproteins and ROS in promoting cancer cell survival and proliferation and treatment strategies employed against these oncoproteins. Antioxid. Redox Signal.

Background We reported that metabolic reprogramming towards OXPHOS-induced drug resistance in oncogene-addicted tumors. OXPHOS is an attractive drug target but clinical PD markers of OXPHOS inhibition are lacking. We present interim PD biomarker data from a dose-finding/phase IIa study of OPC in an advanced cancer population enriched for molecular pathway-driven tumors. Methods After the dose-finding phase of OPC monotherapy at 3 levels (600mg, 400mg, 300mg), the study is now enrolling HER2+ breast cancer, EGFR+ NSCLC and c-KIT+ GIST patients to receive OPC 300mg, 3x/week, 21 days, in combination with their respective pathway inhibitors. Baseline (BL) and C1D15 tumor biopsies were analysed for mitochondrial DNA (mtDNA) copy number [qPCR] and immunohistochemistry (IHC) markers of mitochondrial biogenesis/OXPHOS [PGC1α, TFAM, SIRT1] and cancer stem cells [ALDH1A2]. Blood collected on days 1, 4/5 and 11/12 was analysed by flow cytometry of PBMCs for mitochondrial membrane potential (MMP) and serum metabolomics of amino/organic acids by LC-MS/GC-MS. Results 13 patients (8 with molecular pathway-activated cancers) have been enrolled so far; 5 had evaluable paired biopsies. There were no G3/4 toxicities at the 300mg dose level (n = 8). Tumor mtDNA copy number declined significantly with treatment (-45.0 + 6.0%, C1D15 vs BL, p = 0.006). The expected decrease in IHC expression of ALDH1A2, TFAM, PGC1α (C1D15 vs BL) occurred in 80% (4/5), 60% (3/5) and 40% (2/5), respectively; expected rebound increase in SIRT1 expression was seen in 80% (4/5). Serum metabolomics (C1D4 vs BL) showed significant increase in TCA intermediates, citrate (+18.7 + 14.2%, p = 0.004) and fumarate (+29.7 + 37.1%, p = 0.043), indicative of NADH accumulation following OXPHOS inhibition. There was a non-significant rise in serum lactate (+17.2+ 27.1%, p = 0.094) and reduction in PBMC MMP [0.71 + 0.67 vs 0.29 + 0.23, BL vs C1D11/12, p = 0.068] (n = 11). Conclusions We identified novel tumor/blood PD biomarkers with clear evidence of target modulatory effects at clinically tolerable doses of OPC. With validation, they can aid the clinical development of OXPHOS inhibitors as a novel class of cancer therapy. Clinical trial identification NCT03158324. Legal entity responsible for the study Otsuka Pharmaceutical Co. Ltd. Funding Otsuka Pharmaceutical Co. Ltd. Disclosure D.S. Tan: Honoraria (self): Roche; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): MSD; Honoraria (self): Genmab; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Merck Serono; Honoraria (self): Tessa Therapeutics; Honoraria (self): Novartis; Research grant / Funding (self): Karyopharm. R. Sundar: Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self): Lilly; Advisory / Consultancy: Eisai; Research grant / Funding (self): Paxman; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Taiho Pharmaceutical. J.S. Lim: Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Synthon; Travel / Accommodation / Expenses: AstraZeneca. N. Ohi: Full / Part-time employment: Fujii Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd., Shiga, Japan. T. Tsunoda: Full / Part-time employment: Otsuka Pharmaceutical Co. Ltd., Tokyo, Japan. B. Goh: Research grant / Funding (institution): Otsuka Pharmaceutical Co. Ltd. A.L. Wong: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: Eisai; Research grant / Funding (institution): Otsuka Pharmaceutical Co Ltd. All other authors have declared no conflicts of interest.

Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism., Highlights • Metabolic reprogramming of cancer cells is one of the hallmarks of cancer. • STAT3 and OXPHOS upregulation are resistance mechanisms in oncogene-addicted tumors. • mSTAT3 has a role in the direct, non-transcriptional regulation of OXPHOS. • Combining OXPHOS inhibitors with TKIs reverses resistance to targeted therapy.