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Journal Article•DOI•

Metabolic Reprogramming in Anticancer Drug Resistance: A Focus on Amino Acids.

Erica Pranzini1, Elisa Pardella1, Paolo De Paoli1, Sarah-Maria Fendt2, Maria Letizia Taddei1 •
University of Florence1, Katholieke Universiteit Leuven2
15 Mar 2021-Trends in cancer (Cell Press)-Vol. 7, Iss: 8, pp 682-699
TL;DR: Recent evidence highlighting the key role of amino acid (AA) metabolic reprogramming in cancer cells and the supportive microenvironment in driving resistance to anticancer therapies is provided.
Abstract: Overcoming anticancer drug resistance is a major challenge in cancer therapy, requiring innovative strategies that consider the extensive tumor heterogeneity and adaptability. We provide recent evidence highlighting the key role of amino acid (AA) metabolic reprogramming in cancer cells and the supportive microenvironment in driving resistance to anticancer therapies. AAs sustain the acquisition of anticancer resistance by providing essential building blocks for biosynthetic pathways and for maintaining a balanced redox status, and modulating the epigenetic profile of both malignant and non-malignant cells. In addition, AAs support the reduced intrinsic susceptibility of cancer stem cells to antineoplastic therapies. These findings shed new light on the possibility of targeting nonresponding tumors by modulating AA availability through pharmacological or dietary interventions.

Summary (3 min read)

Jump to: [Resistance: A Focus on Amino Acids] – [The Multifaceted Factors behind Anticancer Drug Resistance] – [Strategies] – [Amino Acids Drive Epigenetic Modulation of Drug-Resistant Cancer Cells] – [Tumor Microenvironment-Derived Amino Acids Confer Anticancer Therapy Resistance] – [Key Figure] – [Amino Acid Metabolic Regulation of Cancer Stem Cells Supports Cancer Aggressiveness] – [Modulation of Amino Acid Availability for Cancer Therapy] – [Concluding Remarks and Future Perspectives] – [Acknowledgments] and [Declaration of Interests]

Resistance: A Focus on Amino Acids

  • Cancer cells establish metabolic crosstalk with cellular and non-cellular components of the tumor microenvironment that finally provides cancer cells with the nutrients necessary to support anticancer therapy resistance and cancer immune escape.
  • In addition, AAs support the reduced intrinsic susceptibility of cancer stem cells to antineoplastic therapies.
  • Tus of all the components of the tumor, thereby contributing to the anticancer drug-resistance phenotype.
  • Approaches targeting AA availability in the tumor microenvironment could be valid supportive tools for therapeutic interventions aimed at counteracting drug resistance.

The Multifaceted Factors behind Anticancer Drug Resistance

  • Drug resistance currently remains a major challenge for cancer cure.
  • The emergence of resistant clones results from the selection of both pre-existing and drug-induced resistance-mediating factors, which can be achieved by genetic and epigenetic alterations [1], together with the influence of the tumor microenvironment (TME) (see Glossary) [2] and the presence of cancer stem cells (CSCs) [3].
  • Growing attention has been directed to the immense heterogeneity of tumor metabolism (Box 1).
  • Drug-induced selective pressures favor the emergence of specific metabolic traits that confer the best resistance strategy.
  • In this review the authors summarize recent findings demonstrating how cancer cells and the supportive microenvironment adapt their AA metabolism to overcome drug toxicity.

Strategies

  • The role of AAs is becoming an attractive topic in the field of cancer metabolism.
  • Chemical reactions which replenish a metabolic pathway of depleted intermediates, also known as Glossary Anaplerotic reactions.
  • In anticancer therapy ET is employed to decrease malignant cell proliferation by modulating hormone-dependent pathways.
  • In these cases, resistant cells adapt their metabolism to generate the crucial mediators of cellular redox balance, NADPH and reduced glutathione (GSH), allowing them to strengthen their antioxidant capacity and overcome reactive oxygen species (ROS)induced cell death [12].
  • The upregulation of the glutamine/glutamate axis flux allows resistant cells to potentiate GSH generation, thus counteracting CPT-induced oxidative stress.

Amino Acids Drive Epigenetic Modulation of Drug-Resistant Cancer Cells

  • Epigenetic regulations are emerging as key contributors to anticancer drug resistance, and modulating the availability of AAs implicated in the epigenetic program is a promising strategy to target the transcriptional plasticity of therapy-resistant cancer cells.
  • Indeed, methionine deprivation is sufficient to deplete SAM levels, thereby inducing epigenetic Trends in Cancer, Month 2021, Vol. xx, No. xx 3 changes [30] and allowing cancer cells to both epigenetically modulate resistance-related gene expression and impair the anticancer immune response.
  • The emergence of neuroendocrine prostate cancer (NEPC), an aggressive variant of prostate cancer that is resistant to androgen receptor (AR) targeted therapies, is promoted by mTORC1/activating transcription factor 4 (ATF4)-mediated upregulation of SSP and the consequent rise in SAM-mediated DNA methylation that is responsible for NEPC differentiation [33].
  • Notably, the metabolic dependency of cellular epigenetic status may underlie the selection of resistant clones in specific regions of solid tumors according to the heterogeneity of nutrient distribution.
  • In different in vivo xenograft models of melanoma, dietary glutamine supplementation can resensitize BRAFiresistant cells by increasing αKG-dependent hypomethylation of H3K4me3 [35].

Tumor Microenvironment-Derived Amino Acids Confer Anticancer Therapy Resistance

  • The efficacy of a therapeutic approach is strongly influenced by the dynamic crosstalk established among all the components of the TME.
  • Increasing evidence demonstrates that a single 'cancer metabolic profile' cannot be defined.
  • Intratumor heterogeneity derives from intrinsic and extrinsic factors [118] (Figure I).
  • Conversely, cancer and immune cells share several metabolic features, resulting in nutritional competition that further increases the heterogeneity of the TME composition [130,131].
  • Glutamine provides cancer cells with carbons and nitrogens for protein, fatty acid, and nucleotide biosynthesis.

Key Figure

  • Amino Acid (AA) Metabolism in Cancer (Figure legend continued at the bottom of the next page.).
  • The antimetabolites 5-fluorouracil (5-FU) and methotrexate (MTX) interfere with nucleotide metabolism by disrupting folate cycle flux through the inhibition of thymidylate synthase (TS) and dihydrofolate reductase (DHFR), respectively.
  • Exogenous glutamine concurrently favors cancer cell growth and the generation of a protumoral immunosuppressive microenvironment.
  • T cell activation, promoting cytotoxic T lymphocyte (CTL) infiltration, and protecting intratumor CTLs from exhaustion [52].
  • Moreover, PDAC cells are able to directly take up extracellular 10 Trends in Cancer, Month 2021, Vol. xx, No. xx collagen and utilize collagen-derived proline to support the tricarboxylic acid (TCA) cycle via proline dehydrogenase 1 (PRODH1) upregulation under nutrient deficiency.

Amino Acid Metabolic Regulation of Cancer Stem Cells Supports Cancer Aggressiveness

  • Eliminating the CSC subpopulation represents a major challenge in cancer therapy because of their intrinsic lower sensitivity to antineoplastic agents.
  • The xc− system thus represents a promising target for immunotherapy against undifferentiated cancer cells.
  • In addition to the xc− system, glutamine also participates in maintaining redox balance in CSCs.
  • Indeed, abundant exogenous serine is essential for the expansion of tumorinitiating EpdSCs.
  • Similarly, in patient-derived AML stem cells, that are characterized by an upregulated BCAA degradation pathway, knockdown of BCAT1 results in αKG accumulation and increased αKG-dependent dioxygenase activity, leading to HIF1α protein degradation and suppression of tumor-initiating potential both in vitro and in vivo [73].

Modulation of Amino Acid Availability for Cancer Therapy

  • Given that AA metabolism adaptations contribute to acquired resistance to different antineoplastic agents, targeting these specific vulnerabilities has recently emerged as a strategy to develop successful anticancer therapy tools.
  • Of note, different studies recently demonstrated that the efficacy of rMETasebased therapy is further potentiated in combination with other chemotherapeutic agents [91,92].
  • In addition, dietary AA deprivation and/or supplementation are emerging as novel promisingmethods to overcome chemotherapy resistance and delay cancer progression [93].
  • Given its pleiotropic role in tumor progression, together with pharmacological inhibition, dietary modulation of glutamine metabolism is one of the most-investigated therapeutic approaches, and demonstrates promising efficacy in suppressing tumor growth in various cancer types both in vitro and in vivo [94].
  • Similarly, methionine supplementation leads to increased T cell immunity [31], whereas methionine restriction impairs cancer cell growth, further underlining the importance of selectively targeting AA metabolism in different cell populations.

Concluding Remarks and Future Perspectives

  • It has long been known that cancer cells can reprogram their metabolism to overcome stressful conditions and adapt their energy and biosynthetic needs.
  • Indeed, given the absence of toxicity and easy patient acceptability, dietary modulation of specific AAs is yielding good results.
  • In adopting these strategies, attention must be addressed to some key aspects.
  • Indeed, the individual genetic alterations and the metabolic profile of the parental tissue may provide cancer cells with a specific sensitivity to dietary modulation (see Outstanding Questions).
  • In conclusion, the crucial role of AA metabolism in driving the adaptive response of resistant cancers opens the possibility for novel therapeutic approaches to overcome therapy resistance, although both the genetic background of the tumor and the composition of the TME must be taken into consideration.

Acknowledgments

  • S.M.F. acknowledges funding from the European Research Council (ERC) under consolidator grant agreement 771486– MetaRegulation, Fonds Wetenschappelijk Onderzoek (FWO) research projects, KU Leuven Methusalem Co-Funding, and Fonds Baillet Latour.
  • M.L.T and P.P. acknowledge funding from the University of Florence (Fondo ex-60%).
  • P.P acknowledges funding from the Associazione Italiana Ricerca sul Cancro (AIRC) (project 19515 'Assaying tumor metabolic deregulation in live cells').
  • EP is supported by an Associazione Italiana per la Ricerca sul Cancro (AIRC) fellowship (project 24132, 'Metabolic adaptations driving epigenetics of 5-fluorouracil-resistant colon cancer: the role of one carbon metabolism').

Declaration of Interests

  • S.M.F. has received funding from Bayer AG, Merck, and Black Belt Therapeutics, and has consulted for Fund +.
  • The other authors declare no conflicts of interest.

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Citations
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TL;DR: Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA use, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumorformation, arguing that tissue of origin is an important determinant of how cancers satisfy their metabolic requirements.
Abstract: Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non–small cell lung carcinoma (NSCLC), respectively, but despite the same initiating events, these tumors use branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source, whereas PDAC tumors have decreased BCAA uptake. These differences are reflected in expression levels of BCAA catabolic enzymes in both mice and humans. Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA use, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumor formation, arguing that tissue of origin is an important determinant of how cancers satisfy their metabolic requirements.

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Frequently Asked Questions (27)
Q1. What is the role of the SSP in BTZ-resistant cells?

Strong upregulation of the serine synthesis pathway (SSP) allows BTZ-resistant cells to maintain intracellular levels of GSH in vitro, thus increasing their antioxidant capacity. 

MTX target-related resistancemechanisms include DHFR overexpression or mutations, decreased intracellular drug retention caused by diminished MTX polyglutamylation, and intracellular THF accumulation. 

In patient-derived lung adenocarcinoma cells and xenograft models, mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is essential to confer stem-like properties through the β-catenin pathway and ensure TKi-gefitinib resistance by modulating purine metabolism. 

In conclusion, the crucial role of AA metabolism in driving the adaptive response of resistant cancers opens the possibility for novel therapeutic approaches to overcome therapy resistance, although both the genetic background of the tumor and the composition of the TME must be taken into consideration. 

The authors provide recent evidence highlighting the key role of amino acid ( AA ) metabolic reprogramming in cancer cells and the supportive microenvironment in driving resistance to anticancer therapies. 

In addition, modulating plasma AA levels by pharmacological or dietary intervention is a promising option to improve anticancer therapies. 

Many tumors increase the endogenous serine synthesis pathway (SPP), primarily by overexpressing phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway. 

Pharmacological depletion of specific AAs is an effective strategy to decrease their circulating levels and target auxotrophic tumors. 

IDO1 overexpression generates an immunosuppressive microenvironment by depleting extracellular tryptophan necessary for T cell proliferation and facilitates the accumulation of kynurenine that supports 

In addition, MYC mediates increased dependency on the enzymes implicated in serine/glycine metabolism to fuel one-carbon metabolism and purine biosynthesis [29]. 

The cysteine/glutamate exchange transporter xc− imports the AA Cys-Cys, the oxidized form of Cys, into cells in exchange for Glu to support cellular GSH synthesis. 

Met metabolism participates in the folate cycle by providing THF, and is essential for the generation of S-adenosyl methionine (SAM). 

Blocking aspartate production in bone marrow stromal cells (BMSCs) partially sensitizes AML cells to iCT, confirming the chemoprotective effect of BMSC-derived aspartate [41]. 

ITE is essential to revert the stemness phenotype by inhibiting the transcription of the master pluripotency factor Oct4, and finally reduces the tumorigenicity of stem-like cancer cells in different in vivo tumor models [71]. 

Among others, cysteine is fundamental for LSC survival, and treatment with the cysteine-degrading enzyme, cyst(e)inase, effectively eradicates LSCs derived from patients with both de novo and relapsed AML [63]. 

The emergence of neuroendocrine prostate cancer (NEPC), an aggressive variant of prostate cancer that is resistant to androgen receptor (AR) targeted therapies, is promoted by mTORC1/activating transcription factor 4 (ATF4)-mediated upregulation of SSP and the consequent rise in SAM-mediated DNA methylation that is responsible for NEPC differentiation [33]. 

methionine restriction acts as a stronger inhibitor of PDX colorectal cancer growth when provided 2 weeks before tumor inoculation, suggesting that this dietary intervention may exert its effects at the early stages of tumorigenesis [10]. 

cancer cells also generate a 'temporal heterogeneity' by changing their metabolism over time according to the ongoing process of cancer progression. 

targetingmetabolic crosstalk between tumor cells and the surrounding TME represents an attractive alternative strategy to inhibit tumor growth. 

Approaches targeting AA availability in the tumor microenvironment could be valid supportive tools for therapeutic interventions aimed at counteracting drug resistance. 

In particular, the intracellular content of glutamine-derived α-ketoglutarate (αKG) is significant because it supports the activity of the Jumonji domaincontaining histone lysine demethylases. 

Both ER+ and ER− breast CSCs (BCSCs) display upregulation of PHGDH under hypoxic conditions, and consequently PHGDH knockdown strongly abrogates the enrichment of ALDH+ 

A possible strategy to maximize the therapeutic potential of these approaches could be to modulate the dietary intervention according to the composition of the tumor immune infiltrate in a patient-specific manner. 

In conclusion, the crucial role of AA metabolism in driving the adaptive response of resistant cancers opens the possibility for novel therapeutic approaches to overcome therapy resistance, although both the genetic background of the tumor and the composition of the TME must be taken into consideration. 

The most common therapeutic approach is represented by the pharmacological inhibition of specific enzymes involved in cancer AA metabolism (reviewed in [79,80]). 

the metabolic dependency of cellular epigenetic status may underlie the selection of resistant clones in specific regions of solid tumors according to the heterogeneity of nutrient distribution. 

In addition, cyst(e)inase treatment displays a greater efficacy in affecting chronic lymphocytic leukemia (CLL) compared with the standard-of-care drug, fludarabine, in both in vitro models and primary leukemia cells isolated from CLL drug-resistant patients [83].