Targeted Inhibition of EGFR and Glutaminase Induces Metabolic Crisis in EGFR Mutant Lung Cancer

Abstract

Cancer cells exhibit increased use of nutrients including glucose and glutamine to support the bioenergetic and biosynthetic demands of proliferation. We tested the small molecule inhibitor of glutaminase CB-839 in combination with erlotinib on EGFR mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMPK pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-Glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following CB-839 + erlotinib treatment. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to non-invasively measure metabolic response to CB-839 and erlotinib combination therapy.

The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma

“…We conducted serial PET imaging of KL mice with 18 F-FDG and 11 C-Gln within the same week as previously described (Momcilovic et al, 2017) (Figure S2). Representative images are shown in Figure 2A.…”

“…The experiments were performed as described previously (Momcilovic et al, 2017; Thai et al, 2014). Briefly, 5–10 mg of frozen tissue was homogenized in 1 ml 80% methanol (−80°C), centrifuged for 5 min at top speed (4°C) and supernatant was transferred to a separate tube.…”

“…Tissue isolation, fixation and staining procedures were performed as previously described (Momcilovic et al, 2017; Momcilovic et al, 2015; Shackelford et al, 2013). Briefly, lungs or tumors were fixed overnight in 10% buffered formalin, and then transferred to 70% ethanol.…”

Metabolic Alterations in Cancer and Their Potential as Therapeutic Targets

“…More recently, however, several small-molecule allosteric inhibitors of glutaminase activity have been identified, including CB-839, currently in clinical trials, and BPTES. Targeting glutaminase activity has been shown to reduce oncogenic transformation in cancer cells 38 and allosteric inhibitors of glutaminase have been used in combination with other chemotherapeutics to reduce tumor cell growth in lymphoma 39 , lung 40 , and breast 41 cancer cell lines. Further research will likely focus on determining which tumors are most glutamine-dependent, and thus most susceptible to glutaminase inhibition.…”

Immunotherapy in tumors failing check-point inhibitors:the sarcoma example – What we missed and where we are heading

“…Within this pathway, glutamine is converted into glutamate, used to make alpha-ketoglutarate (α-KG), important in the Krebs cycle for the synthesis of nucleic and fatty acids. Therefore, interfering with glutamine metabolism can have a profoundly detrimental effect on replicating cells [35][36][37][38]. The Warburg effect has direct consequences in the TME.…”