PubMed · 2826713
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
M R Shetty. 1988. Postsurgical long-term survival.. https://doi.org/10.1200/jco.1988.6.1.184
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
BACKGROUND: Non-small cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), exhibits significant molecular heterogeneity. Ribonucleotide reductase (RNR), composed of RRM1 and RRM2, is essential for DNA synthesis and repair, but its subtype-specific clinical significance in NSCLC remains unclear. OBJECTIVE: To investigate the clinical and prognostic significance of RRM1 and RRM2 expression in NSCLC, with a focus on subtype-specific differences between LUAD and LUSC. METHODS: We analyzed RNA expression and clinical data from 980 NSCLC patients in The Cancer Genome Atlas (TCGA). Associations with clinicopathologic characteristics, overall survival, and oncogenic driver alterations were assessed. RESULTS: In LUAD, high RRM2 expression was significantly associated with advanced pathologic stage (p = 0.004), nodal involvement (p = 0.005), higher T stage (p = 0.030), and gender (p = 0.046). In LUSC, RRM2 was associated with age (p = 0.008), pathologic stage (p = 0.006), and N stage (p = 0.001). RRM1 showed no significant associations with stage-related parameters in either subtype. Correlation analyses revealed modest associations between RRM1 and multiple oncogenic drivers, whereas RRM2 showed stronger subtype-specific correlations, particularly with KRAS/BRAF in LUAD and CDKN2A/SOX2 in LUSC. Kaplan-Meier analysis demonstrated that high expression of both RRM1 and RRM2 was associated with poorer overall survival in LUAD, but not in LUSC. However, neither marker remained significant after adjustment for clinicopathological variables in multivariate analysis. CONCLUSION: RRM2 is associated with tumor progression in both NSCLC subtypes, while the prognostic associations of RRM1 and RRM2 are confined to LUAD. Although neither marker demonstrated independent prognostic significance in multivariate analysis, the findings support subtype-dependent roles of RNR components and highlight the potential biological and therapeutic relevance of nucleotide metabolism pathways in LUAD.
UNLABELLED: EGFR mutations are common oncogenic drivers in non-small cell lung cancer (NSCLC), and approximately half of patients develop brain metastases over the course of their disease. Patients with nonclassic EGFR mutations, such as insertions in exon 20, are a high unmet need with a worse prognosis compared with patients with classic EGFR mutations. Here, we describe the discovery and development of enozertinib (formerly ORIC-114), a highly brain-penetrant, orally bioavailable, irreversible inhibitor that targets EGFR exon 20 mutations with unparalleled kinome selectivity. Preclinical studies revealed strong potency and tumor regressions driven by enozertinib across a broad range of atypical EGFR-mutant models. In a phase I clinical trial of enozertinib in patients with advanced NSCLC bearing atypical mutations in EGFR, a patient harboring an EGFR exon 20 insertion experienced sustained complete response of all systemic and brain metastases. Together, these findings identify enozertinib as a promising investigational inhibitor to address the unmet need for brain-penetrant therapies in NSCLC with EGFR exon 20 insertions or other atypical mutations. SIGNIFICANCE: Preclinical and initial phase I clinical data demonstrate the potency, kinome selectivity, efficacy, and brain penetration of enozertinib in NSCLC with EGFR exon 20 insertions and atypical mutations, warranting further clinical development.
Despite recent treatment advances, non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related deaths worldwide, and therefore it necessitates the exploration of new therapy options. One commonly shared feature of malignant cells is their ability to hijack metabolic pathways to confer survival or proliferation. In this study, we highlight the importance of the polyol pathway (PP) in NSCLC metabolism. This pathway is solely responsible for metabolizing glucose to fructose based on the enzymatic activity of aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD). Via genetic and pharmacological manipulations, we reveal that PP activity is indispensable for NSCLC growth and survival in vitro and in murine xenograft models. Mechanistically, PP deficiency provokes multifactorial deficits, ranging from energetic breakdown and DNA damage, that ultimately trigger the induction of apoptosis. At the molecular level, this process is driven by pro-apoptotic JNK signaling and concomitant upregulation of the transcription factors c-Jun and ATF3. Moreover, we show that fructose, the PP end-product, as well as other non-glycolytic hexoses confer survival to cancer cells and resistance against chemotherapy via sustained NF-κB activity as well as an oxidative switch in metabolism. Given the detrimental consequence of PP gene targeting on growth and survival, we propose PP pathway interference as a viable therapeutic approach against NSCLC.