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Oncogenic KRAS induces arginine auxotrophy in non-small cell lung cancer and confers a therapeutic vulnerability to SLC7A1 inhibition

ABSTRACT: The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer, yet our understanding about the regulatory mechanisms for this pathway in different types of cancer is very limited. In this study, we discover that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silences the expression of arginosuccinate synthase 1 (ASS1), a urea cycle enzyme catalyzing the production of arginine from aspartate and citrulline, and thereby diverts the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication in KRAS-mutant NSCLC. Specifically, KRAS signaling facilitates a hypo-acetylated state in the promoter region of ASS1 gene in a histone deacetylase 3 (HDAC3)-dependent manner, which in turn impedes the recruitment of the transcription factor c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cancer cells impairs the biosynthesis of arginine and renders growth dependency on SLC7A1, an arginine transmembrane transport, to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models obtains a substantial therapeutic benefit in inhibiting KRAS-driven NSCLC growth. Together, our findings uncover a new role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability in treating KRAS-mutant NSCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253688 | GEO | 2024/01/20

REPOSITORIES: GEO

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Project description:Mutant KRAS (mut-KRAS) is present in 30% of all human cancers and plays a critical role in cancer cell growth and resistance to therapy. There is evidence from colon cancer that mut-KRAS is a poor prognostic factor and negative predictor of patient response to molecularly targeted therapy. However, evidence for such a relationship in non small cell lung cancer (NSCLC) is conflicting. KRAS mutations are primarily found at codons 12 and 13, where different base changes lead to alternate amino acid substitutions that lock the protein in an active state. The patterns of mut-KRas amino acid substitutions in colon cancer and NSCLC are quite different, with aspartate (D) predominating in colon cancer (50%) and cysteine (C) in NSCLC (47%). Through an analysis of a recently completed biopsy biomarker-driven, molecularly targeted multi-arm trial of 215 evaluable patients with refractory NSCLC we show that mut-KRas-G12C/V but not total mut-KRAS predicts progression free survival for the overall group, and for the sorafenib and vandetanib treatment arms. Transcriptome microarray data shows differential expression of cell cycle genes between mut-KRas-G12C/V and G12D patient tumors. A panel of NSCLC cell lines with known mut-KRas amino acid substitutions was used to identify pathways activated by the different mut-KRas, showing that mut-KRas-G12D activates both PI-3-K and MEK signaling, while mut-KRas G12C does not, and alternatively activates RAL signaling. This finding was confirmed using immortalized human bronchial epithelial cells stably transfected with wt-KRAS and different forms of mut-KRAS. Molecular modeling studies show that the different conformation imposed by mut-KRas-G12C could lead to altered association with downstream signaling transducers compared to wild type and mut-KRas-G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRas amino acid substitutions signal to effectors in a similar way, and may require different therapeutic interventions. Gene expression profiles were measured in 22 core biopsies from patients with refractory non-small cell lung cancer included in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE). All tumors were KRAS mutants, but with different patterns of amino acid substitutions. Supervised analysis of transcriptome profiling was performed to compare cysteine or valine KRAS mutants with other KRAS mutants.

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Oncogenic KRAS induces arginine auxotrophy in non-small cell lung cancer and confers a therapeutic vulnerability to SLC7A1 inhibition

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