Potential therapeutics using tumor-secreted lactate in nonsmall cell lung cancer

Zi-Xian Liao; Ivan M Kempson; Chia-Chen Hsieh; S-Ja Tseng; Pan-Chyr Yang

doi:10.1016/j.drudis.2021.07.014

Potential therapeutics using tumor-secreted lactate in nonsmall cell lung cancer

Drug Discov Today. 2021 Nov;26(11):2508-2514. doi: 10.1016/j.drudis.2021.07.014. Epub 2021 Jul 27.

Authors

Zi-Xian Liao¹, Ivan M Kempson², Chia-Chen Hsieh¹, S-Ja Tseng³, Pan-Chyr Yang⁴

Affiliations

¹ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.
² Future Industries Institute, University of South Australia, Mawson Lakes, SA 5095, Australia.
³ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan; National Taiwan University YongLin Scholar, YongLin Institute of Health, National Taiwan University, Taipei 10051, Taiwan. Electronic address: sjatseng@ntu.edu.tw.
⁴ Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei 10051, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan. Electronic address: pcyang@ntu.edu.tw.

PMID: 34325010
DOI: 10.1016/j.drudis.2021.07.014

Abstract

Targeted-therapy failure in treating nonsmall cell lung cancer (NSCLC) frequently occurs because of the emergence of drug resistance and genetic mutations. The same mutations also result in aerobic glycolysis, which further antagonizes outcomes by localized increases in lactate, an immune suppressor. Recent evidence indicates that enzymatic lowering of lactate can promote an oncolytic immune microenvironment within the tumour. Here, we review factors relating to lactate expression in NSCLC and the utility of lactate oxidase (LOX) for governing therapeutic delivery, its role in lactate oxidation and turnover, and relationships between lactate depletion and immune cell populations. The lactate-rich characteristic of NSCLC provides an exploitable property to potentially improve NSCLC outcomes and design new therapeutic strategies to integrate with conventional therapies.

Keywords: Lactate; Lactate oxidase; NSCLC; Nanoparticles; Nonsmall cell lung cancer; Tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Anaplastic Lymphoma Kinase / genetics
Animals
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism*
Citric Acid Cycle
Drug Resistance, Neoplasm
Genes, erbB-1 / genetics
Glucose / metabolism
Humans
Immune Checkpoint Inhibitors / therapeutic use
L-Lactate Dehydrogenase / antagonists & inhibitors
Lactic Acid / metabolism*
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Metabolic Networks and Pathways
Mixed Function Oxygenases / therapeutic use
Molecular Targeted Therapy
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins p21(ras) / genetics
Tumor Microenvironment*

Substances

Immune Checkpoint Inhibitors
Protein Kinase Inhibitors
Lactic Acid
Mixed Function Oxygenases
L-Lactate Dehydrogenase
lactate 2-monooxygenase
Anaplastic Lymphoma Kinase
Proto-Oncogene Proteins p21(ras)
Glucose