A5034227503- Melanoma and MAPK Pathways
- Computational Drug Discovery Methods
- Cutaneous Melanoma Detection and Management
- Synthesis and biological activity
- Cancer Genomics and Diagnostics
- Cancer Mechanisms and Therapy
- CRISPR and Genetic Engineering
- PI3K/AKT/mTOR signaling in cancer
- Synthesis of Tetrazole Derivatives
- Cancer Research and Treatments
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Mechanisms of cancer metastasis
- Bone health and treatments
- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- Protein Degradation and Inhibitors
- Protein Kinase Regulation and GTPase Signaling
- CAR-T cell therapy research
- DNA Repair Mechanisms
- Click Chemistry and Applications
- Advanced Fluorescence Microscopy Techniques
- Cytokine Signaling Pathways and Interactions
- Quinazolinone synthesis and applications
- vaccines and immunoinformatics approaches
University of California, Los Angeles
2013-2024
University of Arkansas for Medical Sciences
2022
University of Arkansas at Little Rock
2022
UCLA Health
2019
Nantes Université
2008-2014
Inserm
2008-2014
Westmead Hospital
2012-2013
Royal Prince Alfred Hospital
2013
The University of Sydney
2012-2013
Ludwig Cancer Research
2013
Abstract BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAFV600-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify core pathways and extent tumor heterogeneity during disease progression. show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% disease-progressive tissues, RAS mutations, mutant amplification, alternative splicing being most common. also PI3K–PTEN–AKT–upregulating...
Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies sequential and/or combinatorial regimens in subcutaneous murine models melanoma driven by BrafV600, Nras, or Nf1 mutations as well colorectal pancreatic carcinoma KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response...
Abstract Extrachromosomal DNA (ecDNA) is a common mode of oncogene amplification but challenging to analyze. Here, we adapt CRISPR-CATCH, in vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis agarose-entrapped genomic DNA, previously developed for bacterial chromosome segments, isolate megabase-sized human ecDNAs. We demonstrate strong enrichment ecDNA molecules containing EGFR , FGFR2 MYC from cancer cells NRAS metastatic melanoma with acquired therapeutic resistance. Targeted...
Blocking cancer genomic instability may prevent tumor diversification and escape from therapies. We show that, after MAPK inhibitor (MAPKi) therapy in patients mice bearing patient-derived xenografts (PDX), acquired resistant genomes of metastatic cutaneous melanoma specifically amplify resistance-driver, nonhomologous end-joining (NHEJ), homologous recombination repair (HRR) genes via complex rearrangements (CGR) extrachromosomal DNAs (ecDNA). Almost all sensitive acquired-resistant harbor...
BRAF inhibitor (BRAFi) therapy leads to remarkable anti melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence selection pattern genetic variants, causing late, acquired resistance. We show here that (or + MEKi) in patients frequently led rebound phosphorylated AKT (p-AKT) levels their melanomas on-treatment. In cell lines, treatment of receptor...
Treatment of advanced
V600 BRAF mutations drive approximately 50% of metastatic melanoma which can be therapeutically targeted by inhibitors (BRAFi) and, based on resistance mechanisms, the combination and MEK (BRAFi + MEKi). Although therapy has been shown to provide superior clinical benefits, acquired is still prevalent limits overall survival benefits. Recent work that oncogenic changes lead alterations in tumor cell metabolism rendering cells addicted nutrients, such as amino acid glutamine. Here, we...
Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms addiction in MAPKi-resistant
BRAF inhibitors (BRAFi) induce antitumor responses in nearly 60% of patients with advanced V600E/KBRAF melanomas. Somatic activating MEK1 mutations are thought to be rare melanomas, but their potential concurrence may selected for by BRAFi. We sequenced MEK1/2 exon 3 melanomas at baseline and upon disease progression. Of 31 5 (16%) carried concurrent somatic BRAF/MEK1 mutations. Three double-mutant showed objective tumor responses, consistent the overall frequency. No mutation was found...
Abstract Despite recent improvements in therapeutic management of osteosarcoma, ongoing challenges improving the response to chemotherapy warrants new strategies still needed improve overall patient survival. In this study, we investigated vivo effects RAD001 (Everolimus), a orally available mTOR inhibitor, on growth human and mouse osteosarcoma cells either alone or combination with zoledronate (ZOL), an anti-osteoporotic drug used treat bone metastases. inhibited cell proliferation dose-...
Abstract A prominent mechanism of acquired resistance to BRAF inhibitors in V600 -mutant melanoma is associated with the upregulation receptor tyrosine kinases. Evidences suggested that this part a more complex cellular adaptation process. Using an integrative strategy, we found invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations accompany transition de-differentiated, mesenchymal invasive state. Even short-term BRAF-inhibitor exposure leads early adaptive,...
MAPK targeting in cancer often fails due to reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining type II RAF (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers KRAS, NRAS, NF1, BRAF non-V600, V600 mutations. Tumor cell-intrinsically, RAFi plus sequester complexes, reduce MEK/MEK dimerization, uncouple from ERK acquired-resistant...
Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model dual MAPK inhibitor (MAPKi) bears BRAFV600 through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E displayed mode switching between DMs HSRs, from both de novo genetic...
Abstract MAPK inhibitor (MAPKi) therapy in melanoma leads to the accumulation of tumor-surface PD-L1/L2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that E3 ligase ITCH binds, ubiquitinates, downregulates PD-L1/L2 MAPKi-treated human cells, thereby promoting T-cell activation. During MAPKi vivo, cell–intrinsic knockdown induced PD-L1, reduced intratumoral cytolytic CD8+ T accelerated resistance only immune-competent mice. Conversely, tumor...
Abstract Metastasis and failure of present-day therapies represent the most common causes mortality in patients with cutaneous melanoma. To identify underlying genetic transcriptomic landscapes, this study we analyzed multi-organ metastases tumor-adjacent tissues from 11 rapid autopsies after treatment MAPK inhibitor (MAPKi) and/or immune checkpoint blockade (ICB) death due to acquired resistance. Either elicits shared alterations that suggest immune-evasive, cross-therapy resistance...
Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack response to chemotherapeutic treatments shows importance exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for treatment chronic myeloid leukemia. Several studies revealed that imatinib inhibits osteoclast differentiation through M-CSFR pathway and activates osteoblast...
We report the development of high-speed live-cell interferometry (HSLCI), a new multisample, multidrug testing platform for directly measuring tumor therapy response via real-time optical cell biomass measurements. As proof concept, we show that HSLCI rapidly profiles changes in BRAF inhibitor (BRAFi)-sensitive parental melanoma lines and their isogenic BRAFi-resistant sublines. reproducible results from two different platforms at institutions generate kinetic signatures capable...
Functional evaluation of genetic lesions can discover a role in cancer initiation and progression help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as tumor suppressor KIT-driven melanoma. Here, we show that is also frequently deleted human melanoma driven by mutant BRAF. found inactivation cell lines primary zebrafish conferred resistance to BRAFV600E inhibition vitro vivo. Mechanistically, loss promoted proliferation under BRAF...