Hyperactivation of TORC1 Drives Resistance to the Pan-HER Tyrosine Kinase Inhibitor Neratinib in HER2-Mutant Cancers

Publication date: Available online 23 January 2020Source: Cancer CellAuthor(s): Dhivya R. Sudhan, Angel Guerrero-Zotano, Helen Won, Paula González Ericsson, Alberto Servetto, Mariela Huerta-Rosario, Dan Ye, Kyung-min Lee, Luigi Formisano, Yan Guo, Qi Liu, Lisa N. Kinch, Monica Red Brewer, Teresa Dugger, James Koch, Michael J. Wick, Richard E. Cutler, Alshad S. Lalani, Richard Bryce, Alan AuerbachSummaryWe developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research

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CONCLUSIONS.: Our results confirm the multidimensional nature of mania. Hyperactivity, increased speech, and thought disorder appear as core features of the clinical construct. The mood experience could be heterogeneous, depending on the co-occurrence of euphoric (elevated mood) and dysphoric (irritability and depressive mood) emotions of varying intensity. Results are also discussed regarding their relationship with other constitutive elements of bipolar disorder, such as mixed and depressive states. PMID: 32093802 [PubMed - in process]
Source: Journal of the Association of European Psychiatrists - Category: Psychiatry Tags: Eur Psychiatry Source Type: research
Authors: Biederman J, DiSalvo M, Woodworth KY, Fried R, Uchida M, Biederman I, Spencer TJ, Surman C, Faraone SV Abstract BACKGROUND.: A growing body of research suggests that deficient emotional self-regulation (DESR) is common and morbid among attention-deficit/hyperactivity disorder (ADHD) patients. The main aim of the present study was to assess whether high and low levels of DESR in adult ADHD patients can be operationalized and whether they are clinically useful. METHODS.: A total of 441 newly referred 18- to 55-year-old adults of both sexes with Diagnostic and Statistical Manual of Mental Disorders: Fifth...
Source: Journal of the Association of European Psychiatrists - Category: Psychiatry Tags: Eur Psychiatry Source Type: research
Source: Cancer Genetics and Cytogenetics - Category: Genetics & Stem Cells Source Type: research
Hi guys, I'm trying to gauge where I stand and am very confused due to my weird background. I took the MCAT in Jan and received a 524, but my GPAs are on the lower end. I am AA URM. GPA: 3.66c, 3.73s, 1 year 4.0 at end || 3.5 masters, 3.5 PhD first year (left see below) MCAT: 524 || Balanced, first take State: CA Race: URM, AA Clinical Volunteering: 250 hours - general hospital volunteer pulm unit 200 hours - driver for american cancer society patients 280... 3.66 cGPA, 3.73sGPA, 524 MCAT URM
Source: Student Doctor Network - Category: Universities & Medical Training Authors: Tags: What Are My Chances? WAMC Medical Source Type: forums
Publication date: Available online 25 February 2020Source: The Lancet Respiratory MedicineAuthor(s): Tony Kirby
Source: The Lancet Respiratory Medicine - Category: Respiratory Medicine Source Type: research
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Publication date: 1 June 2020Source: Personality and Individual Differences, Volume 159Author(s): Donald H. Saklofske
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Source: Gynecologic Oncology Reports - Category: OBGYN Source Type: research
Conclusion: These updated French guidelines will contribute to increase the level of urological care for the diagnosis and treatment for NMIBC and MIBC. PMID: 32093463 [PubMed - in process]
Source: Progres en Urologie - Category: Urology & Nephrology Tags: Prog Urol Source Type: research
Publication date: Available online 25 February 2020Source: The Lancet HIVAuthor(s): Fengyi Jin, I Mary Poynten, Andrew E Grulich
Source: The Lancet HIV - Category: Infectious Diseases Source Type: research
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