Drug tolerance is a major cause of relapse after cancer treatment. Despite intensive efforts, its molecular basis remains poorly understood, hampering actionable intervention. We report a previously unrecognized signaling mechanism supporting drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors that could be of general relevance to other cancers. Its key features are cell-intrinsic intracellular Ca signaling initiated by P2X7 receptors (purinergic ligand-gated cation channels) and an enhanced ability for these Ca signals to reactivate ERK1/2 in the drug-tolerant state. Extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca spikes via P2X7 channels. ATP is abundant in the tumor microenvironment and is released by dying cells, ironically implicating treatment-initiated cancer cell death as a source of trophic stimuli that leads to ERK reactivation and drug tolerance. Such a mechanism immediately offers an explanation of the inevitable relapse after BRAFi treatment in BRAF-mutant melanoma and points to actionable strategies to overcome it.
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http://dx.doi.org/10.3390/cancers16132426 | DOI Listing |
Appl Environ Microbiol
December 2024
Ocean College, Zhejiang University, Zhoushan, China.
This study explored the genomic alterations in , a key yeast in industrial biotechnology, under both spontaneous and mutagen-induced conditions. Our findings reveal that spontaneous mutations occur at a rate of approximately 4 × 10 events per base pair per cell division, primarily manifesting as single-nucleotide variations (SNVs) and small insertions and deletions (InDels). Notably, C-to-T/G-to-A transitions and C-to-A/G-to-T transversions dominate the spontaneous SNVs, while 1 bp deletions, likely resulting from template slippage, are the most frequent InDels.
View Article and Find Full Text PDFFront Psychiatry
December 2024
New York University (NYU) Postdoctoral Program in Psychotherapy and Psychoanalysis, New York University (NYU) Grossman School of Medicine, New York, NY, United States.
Methamphetamine (MA) dependence leads to severe physical and psychological issues. Current treatments, including psychosocial therapies and residential rehabilitation, face limitations such as high relapse rates, cost, and accessibility issues. As a result, there is an urgent need for novel approaches to treat MA dependence that are effective, affordable, and accessible to patients.
View Article and Find Full Text PDFChem Sci
December 2024
Department of Chemistry, School of Chemistry, Xi'an Key Laboratory of Sustainable Energy Material Chemistry, Engineering Research Center of Energy Storage Materials and Devices, Ministry of Education, Xi'an Jiaotong University Xi'an 710049 China
Although bicyclo[4.1.1] systems are privileged scaffolds in many natural products and drug molecules, efficient synthetic approaches to these systems remain underdeveloped.
View Article and Find Full Text PDFPan Afr Med J
December 2024
Laboratoire de Biologie et Santé, Faculté des Sciences, Université Ibn-Tofail, Kenitra, Maroc.
Introduction: the purpose of our study is to evaluate the efficacy of azathioprine as first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS) or progressive multiple sclerosis (PMS), who were supposed to be treated with beta-interferons but, due to limited resources, received azathioprine instead.
Method: among the 31 patients, 17 had relapsing-remitting MS (RRMS), 11 had primary progressive MS (PPMS), and 3 had secondary progressive MS (SPMS). Patients received azathioprine orally at a dose of 3 mg/kg/day over 2 years.
Infect Disord Drug Targets
December 2024
Department of Pharmaceutical Chemistry, Dadasaheb Balpande College of Pharmacy, Nagpur, 440037, Maharashtra, India.
As of early October 2020, the COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, resulted in approximately 35 million cases and one million fatalities worldwide. Systemic lupus erythematosus (SLE) is an autoimmune disease marked by the generation of pathogenic autoantibodies and a lack of tolerance to nuclear self-antigens. Hypocomple-mentemia, or an abnormal blood complement deficit, is a reliable predictor of infection in SLE patients.
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