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Targeting DDX3X suppresses progression of KRAS-driven lung cancer by disrupting antioxidative homeostasis and inducing ferroptosis

ABSTRACT: Approximately 30% of human cancers carry various RAS mutations, including KRAS, NRAS, and HRAS. Among these mutations, KRAS is the most prevalent isoform detected in lung cancer. While several small molecular inhibitors targeting specifically KRASG12C have been developed and tested clinically, alternative approaches are still necessary due to expected drug resistance. In this study, we present evidence that the loss of DDX3X significantly delays tumor progression in various KRAS-driven lung cancer models. Inhibition of DDX3X disrupts cysteine and glutathione metabolism, thereby inducing ferroptosis in lung cancer cells. This effect is primarily mediated by the downregulation of Cystathionine-β-synthase (CBS), the rate-limiting enzyme in cysteine generation. Mechanistically, DDX3X directly binds to the transcription factor JUND, which mediates the transcriptional regulation of METTL16, a key N6-methyladenosine methyltransferase, and subsequently regulates m6A modification and translation of CBS transcripts. This cascade induces hypermethylation and high expression of CBS, consequently triggering cysteine production and maintaining antioxidative homeostasis, which is essential for the survival of KRAS-driven lung cancer cells. Finally, we demonstrate that a newly developed DDX3X PROTAC degrader J10 efficiently delays lung cancer progression with multiple advantages compared to DDX3X small molecular inhibitor RK-33 and limited side effects. These findings unveil the potential of DDX3X as a valuable target for adjuvant therapies in managing KRAS-driven lung cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262058 | GEO | 2025/08/26

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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Targeting DDX3X suppresses progression of KRAS-driven lung cancer by disrupting antioxidative homeostasis and inducing ferroptosis

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