Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer

Abstract

Introduction The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches. Methods We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3. Results MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression. Conclusions Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.

WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC

“…MYC amplification is associated with suppressed immune cell infiltrates and functional pathways ( Wu et al, 2021b ). Although targeting MYC in SCLC has been tested in some preclinical studies ( Cargill et al, 2021 ), there are no defined paths for clinical translation. Furthermore, the effect of immunotherapy in the immunocompetent B6FVBF1/J subcutaneous RPM tumor-bearing model has not yet been demonstrated.…”

In‐depth proteomic analysis reveals unique subtype‐specific signatures in human small‐cell lung cancer

“…Interestingly, proteomic data clearly indicated that the activation of OXPHOS and respiratory chain elements are strongly specific for SCLC-A. It has been recently described that cell lines not expressing MYC (characteristic for SCLC-A 6,8 ) relies more on oxidative metabolism 67 suggesting that SCLC-A tumours might be susceptible to OXPHOS inhibitors. 68 SCLC-N cell lines, which predominantly formed suspension cultures in our study, showed a concordant downregulation of cell adhesion pathways.…”

Killing SCLC: insights into how to target a shapeshifting tumor

“…In addition to differences in cell death regulation, MYC-high/ASCL1-low SCLC tends to be more proliferative and glycolytic with unique metabolic vulnerabilities ( Mollaoglu et al 2017 ; Huang et al 2018a ; Cargill et al 2021 ). Unbiased metabolite profiling experiments on cell lines and murine tumors have identified key metabolic differences in ASCL1-high versus ASCL1-low SCLC subtypes.…”