Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

Abstract

Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and –resistant non-small cell lung cancer.

Lactate in the tumour microenvironment: From immune modulation to therapy

“…Another preclinical study has indicated that combining angiogenesis inhibitors (blocking the VEGF signalling pathway) with AZD3965 inhibits tumour growth and reduces both blood perfusion and hypoxia in tumour tissues [107] . Although studies on the combination of MCT1 inhibitors and tyrosine kinase inhibitors (TKIs) are limited, one preclinical trial has demonstrated that AZD3965 significantly inhibits cell proliferation and motility in TKI-sensitive and TKI-resistant non-small cell lung cancer cells, suggesting that combination therapies have great potential [108] .…”

SIRT1/PGC-1α/PPAR-γ Correlate With Hypoxia-Induced Chemoresistance in Non-Small Cell Lung Cancer

“…High levels of PGC-1α are associated with increased OXPHOS-dependent metabolism in cells, while PGC-1α can also mediate accelerated mitochondrial OXPHOS and glycolysis in the heterogeneous tumor microenvironment ( 156 , 157 ). Additionally, a study investigating the development of NSCLC resistance to EGFR-TKIs found that gefitinib-resistant NSCLC cells acquire metabolic flexibility characterized as a ligand-independent translocation of EGFR to mitochondria, which might contribute to the upregulation of mitochondrial function and capacity for OXPHOS ( 158 ). These observations indicate that the dependence on mitochondrial OXPHOS is a recurrent mechanism of cancer resistance to cisplatin treatment, while PGC-1α-mediated enhancement of mitochondrial biogenesis and OXPHOS is crucial for the development of chemoresistance in NSCLC under hypoxic conditions.…”

Shifting the Gears of Metabolic Plasticity to Drive Cell State Transitions in Cancer

“…It was observed that these cells expressed high levels of MCT-1, which indirectly resulted in enhanced OxPhos, with the upregulation of lactate dehydrogenase B (LDHB). The inhibition of the MCT-1 transporter with the small molecule inhibitor, AZD3965, was able to decrease cell viability, migratory abilities and mitochondrial bioenergetics of cancer cells in serum-limiting conditions [ 121 ]. Similarly, in HER2-driven breast cancer, HER2-targeting TKIs such as lapatinib are often used to treat advanced breast cancer [ 122 , 123 ].…”

“…Early results indicated its tolerability in patients and its anti-tumoral effects when applied in combination with taxanes and gemcitabine [ 174 ]. Similarly, targeting MCT-1 was demonstrated to be effective in reducing the stemness of CSCs, as well as abrogating gefitinib-resistant cells [ 46 , 121 ]. The first-in-human first-in-class trial of the MCT-1 inhibitor, AZD3965, is currently undergoing a Phase I clinical trial for Burkitt lymphoma, diffuse large B cell lymphoma and advanced solid tumors [ 175 ].…”