bims-meluca 2020-10-25 papers

Cancer Discov. 2020 Oct 18. pii: CD-20-0282. [Epub ahead of print]

KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition.

Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0282

Cell Commun Signal. 2020 Oct 23. 18(1): 167

Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells.

Dong Q, Zhou C, Ren H, Zhang Z, Cheng F, Xiong Z, Chen C, Yang J, Gao J, Zhang Y, Xu L, Fang J, Cao Y, Wei H, Wu Z.

BACKGROUND: Metabolic reprogramming contributes significantly to tumor development and is tightly linked to drug resistance. The chemotherapeutic agent etoposide (VP-16) has been used clinically in the treatment of lung cancer but possess different sensitivity and efficacy towards SCLC and NSCLC. Here, we assessed the impact of etoposide on glycolytic metabolism in SCLC and NSCLC cell lines and investigated the role of metabolic rewiring in mediating etoposide resistance.METHODS: glycolytic differences of drug-treated cancer cells were determined by extracellular acidification rate (ECAR), glucose consumption, lactate production and western blot. DNA damage was evaluated by the comet assay and western blot. Chemoresistant cancer cells were analyzed by viability, apoptosis and western blot. Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction.
RESULTS: Here we showed that exposure to chemotherapeutic drug etoposide induces an exacerbation of ROS production which activates HIF-1α-mediated the metabolic reprogramming toward increased glycolysis and lactate production in non-small cell lung cancer (NSCLC). We identified lactic acidosis as the key that confers multidrug resistance through upregulation of multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1), a member of ATP-binding cassette (ABC) transporter family. Mechanistically, lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to induce formation of Snail/TAZ/AP-1 complex at the MRP1/ABCC1 promoter. Induction of MRP1 expression inhibits genotoxic and apoptotic effects of chemotherapeutic drugs by increasing drug efflux. Furthermore, titration of lactic acid with NaHCO3 was sufficient to overcome resistance.
CONCLUSIONS: The chemotherapeutic drug etoposide induces the shift toward aerobic glycolysis in the NSCLC rather than SCLC cell lines. The increased lactic acid in extracellular environment plays important role in etoposide resistance through upregulation of MRP expression. These data provide first evidence for the increased lactate production, upon drug treatment, contributes to adaptive resistance in NSCLC and reveal potential vulnerabilities of lactate metabolism and/or pathway suitable for therapeutic targeting. Video Abstract The chemotherapeutic drug etoposide induces metabolic reprogramming towards glycolysis in the NSCLC cells. The secreted lactic acid coordinates TGF-β1/Snail and TAZ/AP-1 pathway to activate the expression of MRP1/ABCC1 protein, thus contributing to chemoresistance in NSCLC.

Keywords: Chemoresistance; Etoposide; Lactic acid; MRP1; Metabolic reprogramming

DOI: https://doi.org/10.1186/s12964-020-00653-3

Clin Cancer Res. 2020 Oct 19. pii: clincanres.1985.2020. [Epub ahead of print]

NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes.

PURPOSE: Stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in a quarter of lung adenocarcinoma (LUAD) and a third of lung squamous (LUSC) patients. In LUAD, KEAP1 loss often co-occurs with STK11 loss and KRAS activating alterations. Despite its prevalence, the impact of NRF activation on tumor progression and patient outcomes is not fully defined.EXPERIMENTAL DESIGN: We model NRF2 activation, STK11 loss and KRAS activation in vivo using novel genetically engineered mouse models. Further, we derive a NRF2 activation signature from human non-small cell lung tumors that we use to dissect how these genomic events impact outcomes and immune contexture of participants in the OAK and IMpower131 immunotherapy trials.
RESULTS: Our in vivo data reveal roles for NRF2 activation in (i) promoting rapid-onset, multi-focal intra-bronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in KRAS-mutant, STK11-null tumors. In patients with non-squamous tumors, the NRF2 signature is negatively prognostic independently of STK11 loss. LUSC patients with low NRF2 signature survive longer when receiving anti-PD-L1 treatment.
CONCLUSIONS: Our in vivo modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with STK11 loss and KRAS activation to promote aggressive LUAD. In patients, oncogenic events alter the tumor immune contexture, possibly impacting treatment responses. Importantly, patients with NRF2 activated non-squamous or squamous tumors have poor prognosis and show limited response to anti-PD-L1 treatment.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-1985

J Clin Invest. 2020 Oct 20. pii: 139929. [Epub ahead of print]

Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small cell lung cancer.

Huang F, Huffman K, Wang Z, Wang X, Li K, Cai F, Yang C, Cai L, Shih TS, Zacharias LG, Chung AS, Yang Q, Chalishazar MD, Ireland AS, Stewart CA, Cargill KR, Girard L, Liu Y, Ni M, Xu J, Wu X, Zhu H, Drapkin BJ, Byers LA, Oliver TG, Gazdar A, Minna J, DeBerardinis R.

MYC stimulates both metabolism and protein synthesis, but it is unknown how cells coordinate these complementary programs. Previous work reported that in a subset of small cell lung cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here we demonstrated that primary MYCHigh human SCLC tumors also contain abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH links the metabolic and protein synthesis outputs of oncogenic MYC. Co-expression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA Polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functions as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant, MYCHigh SCLC.

Keywords: Intermediary metabolism; Lung cancer; Metabolism; Oncogenes; Oncology

DOI: https://doi.org/10.1172/JCI139929

J Thorac Oncol. 2020 Oct 20. pii: S1556-0864(20)30814-5. [Epub ahead of print]

Dual EGFR/VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC.

Le X, Nilsson M, Goldman J, Reck M, Nakagawa K, Kato T, Ares LP, Frimodt-Moller B, Wolff K, Visseren-Grul C, Heymach JV, Garon EB.

The vascular endothelial growth factor (VEGF) pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptor (VEGFR) have been developed and approved for use in non-small cell lung cancers (NSCLCs). Preclinical studies have shown that the VEGF and epidermal growth factor receptor (EGFR) pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, upregulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs significantly improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs significantly improved progression-free survival in TKI-naïve EGFR-mutant NSCLC patients. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.

Keywords: EGFR; NSCLC; VEGF

DOI: https://doi.org/10.1016/j.jtho.2020.10.006