Catastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN -amplified neuroblastoma

Abstract

MYCN-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an “Achilles’ heel” and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that MYCN-amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in MYCN-amplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in MYCN-amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of MYCN-amplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-blood-cell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for MYCN-amplified neuroblastoma that demonstrates efficacy and tolerability in vivo.

Effects of Lactate Transport Inhibition by AZD3965 in Muscle-Invasive Urothelial Bladder Cancer

“…Patients with advanced metastatic disease or unsuitable for surgery usually undergo treatment with cisplatin-based agents but are highly susceptible to chemoresistance [ 16 ]. Combination studies using AZD3965 demonstrated that this drug is able to enhance radiosensitivity [ 26 ] but also significantly impairs tumor growth in combination with other agents when compared to the effect of either drug alone [ 36 , 38 , 54 ]. Thus, we combined AZD33965 with cisplatin and evaluated their efficacy in impairing cell viability and proliferation.…”

Rho/SRF Inhibitor Modulates Mitochondrial Functions

“…Interestingly, growing evidence suggests a major interest in pursuing the study of mitochondria biology in cancer and targeting this organelle therapeutically [ 37 ]. There are multiple ongoing clinical trials exploring the therapeutic effects of Oxidative Phosphorylation (OXPHOS) inhibitors in different tumor types [ 38 ]. Many preclinical studies have suggested anti-tumor activity of ETC CI inhibitors, for instance, metformin, the most common anti-diabetic drug [ 39 , 40 , 41 ].…”

Oncogenic Chromatin Modifier KAT2A Activates MCT1 to Drive the Glycolytic Process and Tumor Progression in Renal Cell Carcinoma

“…Targeting MCTs was proven to significantly suppress the growth or metastasis of solid tumors, like breast cancer, lung carcinoma, and glioblastoma ( Payen et al, 2020 ; Sandforth et al, 2020 ). Inhibitors of MCT4 are in the discovery phase and AZD3965 (a selective inhibitor) is already in the pre-clinical trials to treat cancers ( Dalton et al, 2021 ; Wang et al, 2021 ). Particularly, previous studies have already indicated that MCT1 was an unfavorable factor in RCC ( Guo et al, 2019 ).…”