A5080697552- Melanoma and MAPK Pathways
- Neuroblastoma Research and Treatments
- Protein Kinase Regulation and GTPase Signaling
- Neurofibromatosis and Schwannoma Cases
- Sarcoma Diagnosis and Treatment
- Cytokine Signaling Pathways and Interactions
- Protein Tyrosine Phosphatases
- PI3K/AKT/mTOR signaling in cancer
- Cancer Mechanisms and Therapy
- Cellular Mechanics and Interactions
- Galectins and Cancer Biology
- Cancer-related Molecular Pathways
- Cancer Research and Treatments
- Integrated Circuits and Semiconductor Failure Analysis
- Cancer-related gene regulation
- Colorectal Cancer Treatments and Studies
- Cellular transport and secretion
- PARP inhibition in cancer therapy
- Mitochondrial Function and Pathology
- Retinal Development and Disorders
- VLSI and Analog Circuit Testing
- Physical Unclonable Functions (PUFs) and Hardware Security
- Cell death mechanisms and regulation
- 14-3-3 protein interactions
- RNA modifications and cancer
University of California, San Francisco
2021-2024
UCSF Helen Diller Family Comprehensive Cancer Center
2021-2024
Babraham Institute
2011-2023
City College of San Francisco
2022
University of Oxford
2014
Naval Surface Warfare Center
2012
Resistance to cancer therapeutics targeting the second kinase in a three-kinase cascade involves amplification of upstream kinase, not inhibited kinase.
The mechanistic target of rapamycin (mTOR) protein kinase coordinates responses to nutrients and growth factors is an anti-cancer drug target. To anticipate how cells will respond adapt chronic mTOR complex (mTORC)1 mTORC2 inhibition, we have generated SW620 colon cancer with acquired resistance the ATP-competitive inhibitor AZD8055 (SW620:8055R). inhibited mTORC1 signalling caused a switch from cap-dependent internal ribosome entry site (IRES)-dependent translation in parental cells. In...
Abstract BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X L expression biases pool towards MCL1. Consequently, or synthetic lethal with MCL1 inhibitor AZD5991, driving profound tumour cell death requires BAK/BAX, inhibiting growth vivo. Combination...
Abstract Background Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects its role as a biomarker in cancer is missing, comprehensive analysis the clinical significance SLFN11 predictive DDA and/or DNA damage-response inhibitor (DDRi) therapies. Methods We used multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies mechanistic studies...
The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient codons 844 to 848, which correlate with a severe phenotype, cause instability and exert an additional dominant-negative action whereby wild-type also becomes destabilized dimerization. used our cryogenic...
Abstract Schwann cell tumors are the most common cancers of peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or type-2 (NF-2). Functional interactions between NF1 NF2 broader mechanisms underlying malignant transformation lineage unclear. Here we integrate bulk single-cell genomics, biochemistry, pharmacology across human samples, lines, mouse allografts to identify cellular de-differentiation driving treatment resistance. We find DNA methylation...
The Semiconductor Industry Associates (SIA) estimates that counterfeiting costs the US semiconductor companies $7.5B in lost revenue, and this is indeed a growing global problem. Repackaging old ICs, selling failed test parts, as well gray marketing, are most dominant practices. Can technology do better job than lawyers? What technical challenges to be addressed? EDA technologies will work: embedding IP protection measures design phase, developing rapid post- silicon certification, or...
Tumour cells typically exhibit a G(1) cell cycle arrest in response to the MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitor selumetinib, but do not die, and thus they acquire resistance. In present study we examined effect of combining selumetinib with BH3 [BCL2 (B-cell lymphoma 2) homology domain 3]-mimetic BCL2 ABT-263. Although either drug alone caused little tumour death, two agents combined cause substantial caspase-dependent...
Abstract Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF V600E or KRAS G13D reinstate ERK1/2 signalling. Here we show that and MEKi are reversible following drug withdrawal. Cells with addicted maintain a precise level signalling is optimal for cell proliferation survival, tumour growth in vivo. Robust activation withdrawal drives p57 KIP2 -dependent G1 cycle arrest senescence expression NOXA death, selecting against those cells amplified . required loss...
RAS proteins are molecular switches that interact with effector when bound to guanosine triphosphate, stimulating downstream signaling in response multiple stimuli. Although several canonical effectors have been extensively studied and tested as potential targets for RAS-driven cancers, many of these remain poorly characterized. In this study, we undertook a biochemical structural approach further study the role Sin1 effector. interacted predominantly KRAS isoform 4A cells through an...
RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and mutated in lung cancer, leukemia, the germline individuals with Noonan syndrome. Pathogenic proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show RAF kinases are direct effectors membrane-bound mutant necessary for MAPK activation. We identify critical residues facilitate interaction membrane lipids...
Innate or acquired resistance to small molecule BRAF MEK1/2 inhibitors (BRAFi MEKi) typically arises through mechanisms that sustain reinstate ERK1/2 activation. This has led the development of a range (ERKi) either inhibit kinase catalytic activity (catERKi) additionally prevent activating pT-E-pY dual phosphorylation by (dual-mechanism dmERKi). Here, we show eight different ERKi (both catERKi dmERKi) drive turnover ERK2, most abundant ERK isoform, with little no effect on ERK1. Thermal...
The image in the top panel of Fig. 1C was erroneously reversed during processing manuscript.
Gene transcription responds to stress and metabolic signals optimize growth survival. Histone H3 (H3) lysine 4 trimethylation (K4me3) facilitates state changes, but how levels are coordinated with the environment is unclear. Here, we show that isomerization of at alanine 15-proline 16 (A15-P16) peptide bond influenced by 14 (K14) controls gene-specific K4me3 balancing actions Jhd2, demethylase, Spp1, a subunit Set1 K4 methyltransferase complex. Acetylation K14 favors A15-P16trans...
Sprouty-related EVH-1 domain-containing (SPRED) proteins are a family of that negatively regulate the RAS-Mitogen-Activated Protein Kinase (MAPK) pathway, which is involved in regulation mitogenic response and cell proliferation. However, mechanism by these affect RAS-MAPK signaling has not been elucidated. Patients with mutations SPRED give rise to unique disease phenotypes; thus, we hypothesized distinct interactions across may account for alternative nodes regulation. To characterize...
The Raf/MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase 1/2]/ERK1/2 signalling pathway is frequently activated in human tumours due to mutations BRAF or KRAS. B-Raf and MEK1/2 inhibitors are currently undergoing clinical evaluation, but their ultimate success likely be limited by acquired drug resistance. We have used colorectal cancer cell lines harbouring K-Ras model resistance the inhibitor selumetinib (AZD6244). Selumetinib-resistant cells were...
Abstract The RAS family GTPases are the most frequently mutated oncogene in human cancers. Activating mutations either of three isoforms (HRAS, KRAS, or NRAS) found nearly 20% all tumors with NRAS ~25% melanomas. Despite remarkable advancements therapies targeted against mutant NRAS-specific pharmacologics lacking. Thus, development inhibitors would address a critical unmet need to treating primary harboring as well BRAF-mutant melanomas, which develop resistance clinically approved BRAF...
Cancer Drug Resistance is an open access journal, focusing on pharmacological aspects of drug resistance and its reversal, molecular mechanisms classes, etc. Both clinical experimental in cancer are included.
BIK (BCL2-interacting killer) is a pro-apoptotic BH3 (BCL2 homology domain 3)-only protein and member of the BCL2 family. It was proposed recently that abundance controlled by ERK1/2 (extracellular-signal-regulated kinase 1/2)-catalysed phosphorylation, which targets for proteasome-dependent destruction. In present study, we examined ERK1/2-dependent regulation BIK, drawing comparisons with BIM(EL) mediator cell death; extra long), well-known target ERK1/2. many tumour lines, inhibition...
Abstract SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates signaling. Mutations in are found several prominent cancer types, including 2-4% of NSCLC, CRC, melanoma. The recent development novel inhibitors (SOS1i), BI-3406, that block interaction between RAS, presents potential therapy SOS1-driven cancers. Here we show the majority mutations observed patients enhance cells activate RAS-MAPK We treated 11 mutant cell lines without co-mutation with...
Abstract SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates signaling. Mutations in are found 3-5% of non-small cell lung cancers (NSCLC), colorectal (CRC) melanomas. The recent development novel inhibitors, including BI-3406 BI-1701963, that block interaction between RAS, presents potential therapy SOS1-driven cancers. Here we show the majority mutations observed patients enhance cells activate RAS-MAPK Of 11 available SOS1-mutant cancer lines...