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Gadgeel, S.

Publications and source records attributed to Gadgeel, S..

2 recordsLinked to original sources

Brief Report: Prognostic relevance of 3q amplification in squamous cell carcinoma of the lung

IntroductionAmplification of 3q is the most common genetic alteration identified in squamous cell carcinoma of the lung (LUSC) with the most frequent amplified region being 3q26-3q28. MethodsIn this analysis, we aim to describe the prognostic relevance of 3q by focusing on a minimal common region (MCR) of amplification within 3q constituted by 25 genes. We analyzed 511 cases of LUSC from The Cancer Genome Atlas (TCGA) and included 476 in the final analysis. ResultsWe identified a 25-gene MCR that was amplified in 221 (44.3%) cases and was associated with better disease specific-survival (DSS) (NR versus 9.25 years; 95% CI [5.24-NR]; log-rank p=0.011) and a progression-free interval (PFI) of 8 years (95% CI [5.1-NR]) versus 4.9 years (95% [3.5-NR]) (Log-rank p=0.020). Multivariable analysis revealed MCR amplification was associated with improved DSS and PFI. ConclusionAmplification of the 25-gene MCR within 3q was present in 44% of this cohort mainly composed of Caucasian patients with early-stage LUSC. This analysis is a strong indicator of the prognostic relevance of the 25-gene MCR within 3q. We are further evaluating its prognostic relevance in a racially diverse patient population with advanced LUSC.

genomics↗

Tribbles 2 confers enzalutamide resistance in prostate cancer by promoting lineage plasticity.

Second-generation anti-androgen, such as enzalutamide (Xtandi), is commonly prescribed for prostate cancer therapy, but enzalutamide-resistant, lethally incurable disease invariably develops. To understand the molecular basis of enzalutamide resistance, we comprehensively analyzed prostate tumors and clinically relevant models. These studies revealed that enzalutamide resistant prostate cancer cells overexpress Tribbles 2 (Trib2), a pseudokinase. Expression of Trib2 is negatively regulated by androgen receptor signaling. Overexpression of Trib2 makes prostate cancer cells completely resistant to clinically relevant doses of enzalutamide. Trib2 downregulates expression of luminal markers but upregulates the neuronal transcription factor, BRN2, and the stemness factor, SOX2, to induce neuroendocrine differentiation. Our findings indicate that Trib2 confers resistance to enzalutamide therapy via a mechanism involving increased cellular plasticity and lineage switching.

cancer biology↗