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Publication Record


Identification of a variant in KDR associated with serum VEGFR2 and pharmacodynamics of Pazopanib.
Maitland ML, Xu CF, Cheng YC, Kistner-Griffin E, Ryan KA, Karrison TG, Das S, Torgerson D, Gamazon ER, Thomeas V, Levine MR, Wilson PA, Bing N, Liu Y, Cardon LR, Pandite LN, O'Connell JR, Cox NJ, Mitchell BD, Ratain MJ, Shuldiner AR
(2015) Clin Cancer Res 21: 365-72
MeSH Terms: Adolescent, Angiogenesis Inhibitors, Carcinoma, Renal Cell, Female, Genome-Wide Association Study, Humans, Kidney Neoplasms, Male, Polymorphism, Single Nucleotide, Pyrimidines, Sulfonamides, Vascular Endothelial Growth Factor Receptor-2, Young Adult
Show Abstract · Added February 22, 2016
PURPOSE - VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors.
EXPERIMENTAL DESIGN - We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy.
RESULTS - rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10(-37)). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01).
CONCLUSION - Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors.
©2014 American Association for Cancer Research.
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2 Members
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13 MeSH Terms
Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial.
Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, Kuritzkes DR, Sagar M, Brown TT, Cohn SE, McComsey GA, Aweeka F, Fichtenbaum CJ, Presti RM, Koletar SL, Haas DW, Patterson KB, Benson CA, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS, ACTG A5257 Team
(2014) Ann Intern Med 161: 461-71
MeSH Terms: Adenine, Adult, Atazanavir Sulfate, Darunavir, Deoxycytidine, Drug Combinations, Drug Therapy, Combination, Emtricitabine, Female, HIV Infections, HIV Protease Inhibitors, HIV-1, Humans, Male, Oligopeptides, Organophosphonates, Pyridines, RNA, Viral, Reverse Transcriptase Inhibitors, Sulfonamides, Tenofovir, Therapeutic Equivalency, Viral Load
Show Abstract · Added March 13, 2015
BACKGROUND - Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.
OBJECTIVE - To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability.
DESIGN - A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954).
SETTING - 57 sites in the United States and Puerto Rico.
PATIENTS - Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors.
INTERVENTION - Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d.
MEASUREMENTS - Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability.
RESULTS - Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir.
LIMITATION - The trial was open-label, and ritonavir was not provided.
CONCLUSION - Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen.
PRIMARY FUNDING SOURCE - National Institute of Allergy and Infectious Diseases.
0 Communities
1 Members
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23 MeSH Terms
Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).
Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Lindsley CW, Wood MR
(2014) J Med Chem 57: 7804-10
MeSH Terms: Allosteric Regulation, Animals, Central Nervous System, Drug Discovery, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Indazoles, Male, Piperidines, Rats, Receptor, Muscarinic M5, Substrate Specificity, Sulfonamides
Show Abstract · Added February 19, 2015
A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
0 Communities
1 Members
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14 MeSH Terms
Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.
Yang T, Chun YW, Stroud DM, Mosley JD, Knollmann BC, Hong C, Roden DM
(2014) Circulation 130: 224-34
MeSH Terms: 4-Aminopyridine, Action Potentials, Animals, CHO Cells, Cells, Cultured, Cricetinae, Cricetulus, Drug Evaluation, Preclinical, Female, HEK293 Cells, Humans, Mice, Mice, Inbred C57BL, Models, Animal, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Phenethylamines, Phosphatidylinositol 3-Kinases, Potassium Channel Blockers, Proto-Oncogene Proteins c-akt, Risk Factors, Signal Transduction, Sulfonamides, Torsades de Pointes, Transfection
Show Abstract · Added June 5, 2014
BACKGROUND - New drugs are routinely screened for IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway.
METHODS AND RESULTS - Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in INa-L. Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell-derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A, encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr-blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil).
CONCLUSIONS - Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.
© 2014 American Heart Association, Inc.
0 Communities
2 Members
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26 MeSH Terms
A peptide-based positron emission tomography probe for in vivo detection of caspase activity in apoptotic cells.
Hight MR, Cheung YY, Nickels ML, Dawson ES, Zhao P, Saleh S, Buck JR, Tang D, Washington MK, Coffey RJ, Manning HC
(2014) Clin Cancer Res 20: 2126-35
MeSH Terms: Amino Acid Chloromethyl Ketones, Animals, Apoptosis, Caspase 3, Caspase Inhibitors, Cell Line, Tumor, Colonic Neoplasms, Colorectal Neoplasms, Female, Fluorine Radioisotopes, Fluorobenzenes, Humans, Imidazoles, Immunoblotting, Immunohistochemistry, Indoles, Mice, Inbred C57BL, Mice, Nude, Organophosphates, Peptides, Positron-Emission Tomography, Protein Kinase Inhibitors, Quinazolines, Quinolines, Radiopharmaceuticals, Sulfonamides, Tissue Distribution, Xenograft Model Antitumor Assays
Show Abstract · Added March 20, 2014
PURPOSE - Apoptosis, or programmed cell death, can be leveraged as a surrogate measure of response to therapeutic interventions in medicine. Cysteine aspartic acid-specific proteases, or caspases, are essential determinants of apoptosis signaling cascades and represent promising targets for molecular imaging. Here, we report development and in vivo validation of [(18)F]4-fluorobenzylcarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone ([(18)F]FB-VAD-FMK), a novel peptide-based molecular probe suitable for quantification of caspase activity in vivo using positron emission tomography (PET).
EXPERIMENTAL DESIGN - Supported by molecular modeling studies and subsequent in vitro assays suggesting probe feasibility, the labeled pan-caspase inhibitory peptide, [(18)F]FB-VAD-FMK, was produced in high radiochemical yield and purity using a simple two-step, radiofluorination. The biodistribution of [(18)F]FB-VAD-FMK in normal tissue and its efficacy to predict response to molecularly targeted therapy in tumors was evaluated using microPET imaging of mouse models of human colorectal cancer.
RESULTS - Accumulation of [(18)F]FB-VAD-FMK was found to agree with elevated caspase-3 activity in response to Aurora B kinase inhibition as well as a multidrug regimen that combined an inhibitor of mutant BRAF and a dual PI3K/mTOR inhibitor in (V600E)BRAF colon cancer. In the latter setting, [(18)F]FB-VAD-FMK PET was also elevated in the tumors of cohorts that exhibited reduction in size.
CONCLUSIONS - These studies illuminate [(18)F]FB-VAD-FMK as a promising PET imaging probe to detect apoptosis in tumors and as a novel, potentially translatable biomarker for predicting response to personalized medicine.
©2014 AACR.
1 Communities
3 Members
0 Resources
28 MeSH Terms
Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study.
McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbé C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dréno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A
(2014) Lancet Oncol 15: 323-32
MeSH Terms: Adult, Aged, Dacarbazine, Disease-Free Survival, Female, Follow-Up Studies, Humans, Indoles, Male, Melanoma, Middle Aged, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides, Vemurafenib
Show Abstract · Added March 20, 2014
BACKGROUND - In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups.
METHODS - Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.
FINDINGS - 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events.
INTERPRETATION - Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation.
FUNDING - F Hoffmann-La Roche-Genentech.
Copyright © 2014 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
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16 MeSH Terms
Integrin α1β1 participates in chondrocyte transduction of osmotic stress.
Jablonski CL, Ferguson S, Pozzi A, Clark AL
(2014) Biochem Biophys Res Commun 445: 184-90
MeSH Terms: Animals, Calcium, Cells, Cultured, Chondrocytes, Female, Immunohistochemistry, Integrin alpha1beta1, Leucine, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Microscopy, Confocal, Osmotic Pressure, Signal Transduction, Sulfonamides, TRPV Cation Channels
Show Abstract · Added February 24, 2014
BACKGROUND/PURPOSE - The goal of this study was to determine the role of the collagen binding receptor integrin α1β1 in regulating osmotically induced [Ca(2+)]i transients in chondrocytes.
METHOD - The [Ca(2+)]i transient response of chondrocytes to osmotic stress was measured using real-time confocal microscopy. Chondrocytes from wildtype and integrin α1-null mice were imaged ex vivo (in the cartilage of intact murine femora) and in vitro (isolated from the matrix, attached to glass coverslips). Immunocytochemistry was performed to detect the presence of the osmosensor, transient receptor potential vanilloid-4 (TRPV4), and the agonist GSK1016790A (GSK101) was used to test for its functionality on chondrocytes from wildtype and integrin α1-null mice.
RESULTS/INTERPRETATION - Deletion of the integrin α1 subunit inhibited the ability of chondrocytes to respond to a hypo-osmotic stress with [Ca(2+)]i transients ex vivo and in vitro. The percentage of chondrocytes responding ex vivo was smaller than in vitro and of the cells that responded, more single [Ca(2+)]i transients were observed ex vivo compared to in vitro. Immunocytochemistry confirmed the presence of TRPV4 on wildtype and integrin α1-null chondrocytes, however application of GSK101 revealed that TRPV4 could be activated on wildtype but not integrin α1-null chondrocytes. Integrin α1β1 is a key participant in chondrocyte transduction of a hypo-osmotic stress. Furthermore, the mechanism by which integrin α1β1 influences osmotransduction is independent of matrix binding, but likely dependent on the chondrocyte osmosensor TRPV4.
Copyright © 2014 Elsevier Inc. All rights reserved.
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1 Members
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17 MeSH Terms
Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy.
Johnson DB, Wallender EK, Cohen DN, Likhari SS, Zwerner JP, Powers JG, Shinn L, Kelley MC, Joseph RW, Sosman JA
(2013) Cancer Immunol Res 1: 373-7
MeSH Terms: Adult, Aminoquinolines, Anaphylaxis, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Drug Eruptions, Female, Guillain-Barre Syndrome, Humans, Imiquimod, Indoles, Melanoma, Middle Aged, Nivolumab, Programmed Cell Death 1 Receptor, Skin Neoplasms, Sulfonamides, Vemurafenib
Show Abstract · Added March 20, 2014
Immune checkpoint inhibitors such as ipilimumab and targeted BRAF inhibitors have dramatically altered the landscape of melanoma therapeutics over the past few years. Agents targeting the programmed cell death-1/ligand (PD-1/PD-L1) axis are now being developed and appear to be highly active clinically with favorable toxicity profiles. We report two patients with BRAF V600E mutant melanoma who were treated with anti-PD-1 agents as first-line therapy without significant toxicity, followed by vemurafenib at disease progression. Both patients developed severe hypersensitivity drug eruptions with multi-organ injury early in their BRAF inhibitor treatment course. One patient subsequently developed acute inflammatory demyelinating polyneuropathy (AIDP) and the other developed anaphylaxis upon low-dose vemurafenib rechallenge. Further investigation of the immune response during combination or sequences of melanoma therapeutics is warranted. Furthermore, clinicians should maintain a high index of suspicion for these toxicities when vemurafenib is administered following an anti-PD-1 agent.
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2 Members
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18 MeSH Terms
Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: development of a [3.3.0]-based series and other piperidine bioisosteres.
Sheffler DJ, Nedelcovych MT, Williams R, Turner SC, Duerk BB, Robbins MR, Jadhav SB, Niswender CM, Jones CK, Conn PJ, Daniels RN, Lindsley CW
(2014) Bioorg Med Chem Lett 24: 1062-6
MeSH Terms: Dose-Response Relationship, Drug, Glycine Plasma Membrane Transport Proteins, Humans, Molecular Structure, Piperidines, Structure-Activity Relationship, Sulfonamides
Show Abstract · Added February 19, 2015
This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]-based series displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was observed, within this novel series and a number of other piperidine bioisosteric cores.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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7 MeSH Terms
Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.
Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Chodon T, Guo R, Johnson DB, Dahlman KB, Kelley MC, Kefford RF, Chmielowski B, Glaspy JA, Sosman JA, van Baren N, Long GV, Ribas A, Lo RS
(2014) Cancer Discov 4: 80-93
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Cell Line, Tumor, Clonal Evolution, Drug Resistance, Neoplasm, Female, Humans, Imidazoles, Indoles, Male, Melanoma, Middle Aged, Mitogen-Activated Protein Kinases, Oximes, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, Skin Neoplasms, Sulfonamides, Vemurafenib, ras Proteins
Show Abstract · Added March 20, 2014
BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAF(V600)-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses.
0 Communities
3 Members
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25 MeSH Terms