J. Silvio Gutkind

University of California, San Diego | UCSD · Department of Pharmacology

PIP 3 -dependent Rac exchanger 1 (P–Rex1) is abundantly expressed in neutrophils and plays central roles in chemotaxis and cancer metastasis by serving as a guanine nucleotide exchange factor (GEF) for Rac. The enzyme is synergistically activated by PIP 3 and the heterotrimeric Gβγ subunits, but mechanistic details remain poorly understood. While i...

HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We ap...

The Hippo signaling pathway and its downstream effector YAP play a central role in cell proliferation. Dysregulation of the Hippo pathway triggers YAP hyperactivation, thereby inducing head and neck squamous cell carcinoma (HNSCC). Recently, we reported that EGFR promotes tyrosine phosphorylation of MOB1 and subsequent LATS1/2 inactivation, which a...

The comprehensive genomic analysis of the head and neck cancer (HNSCC) oncogenome revealed frequent loss of p16INK4A (CDKN2A) in most HPV negative HNSCC lesions, often concomitant with amplification of the cyclin D1 (CCND1) gene locus. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as single agents have shown modest effect in the clin...

Tumor initiation represents the initial step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Most studies investigating cancer-driving mechanisms in solid tumors rely on analyses of established malignant lesions, and thus cannot directly capture processes underlying the reprogramming of normal progenito...

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we...

Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we...

With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TI...

Recent advances in immune checkpoint blockade (ICB) inhibiting programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein (CTLA-4) have revolutionized the standard of care for cancer treatment. However, the limited response rates to ICB across multiple cancer types suggest that new approaches and targets are clearly needed to fully elu...

We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets. We derived a network of interacting ligands and biosynthetic enzymes from public databases, that we combined with cognate GPCRs and downstream effectors to quantify GPCR signaling pathways. We found multiple GPCRs differentially regulated together wit...

We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets. We derived a network of interacting ligands and biosynthetic enzymes from public databases, that we combined with cognate GPCRs and downstream effectors to quantify GPCR signaling pathways. We found multiple GPCRs differentially regulated together wit...

Immune checkpoint blockade (ICB) treatment has demonstrated excellent medical effects in oncology, and it is one of the most sought-after immunotherapies for tumors. However, there are several issues with ICB therapy, including low response rates and a lack of effective efficacy predictors. Gasdermin-mediated pyroptosis is a typical inflammatory de...

Heterotrimeric guanine nucleotide-binding proteins (G proteins) that function as molecular switches for cellular growth and metabolism are activated by GTP and inactivated by GTP hydrolysis. In uveal melanoma, a conserved glutamine residue critical for GTP hydrolysis in the G protein α subunit is often mutated in Gαq or Gα11 to either leucine or pr...

BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF–MEK–EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinas...

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead t...

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival ranging from 6 to 18 months. For those who progress on standard of care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we...

Despite encouraging recent results from novel treatment options, such as immunotherapy, for head and neck squamous cell carcinoma (HNSCC), limited progress has been made in improving outcomes for most patients. Prevention and early detection are key to improving the prognosis of HNSCC. Our team has focused on decoding the oncogenic signaling circui...

G proteins and G protein-coupled receptors (GPCRs) activate a diverse array of signal transduction pathways that promote cell growth and survival. Indeed, hotspot activating mutations in GNAQ/GNA11, encoding Gαq proteins, are known to be driver oncogenes in uveal melanoma (UM), for which there are limited effective therapies currently available. Fo...

Somatic copy number alterations (SCNAs), generally ( 1 ) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors ( 2 ); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an...

The mechanistic target of rapamycin (mTOR) plays a key role in normal and malignant cell growth. However, pharmacologic targeting of mTOR in cancer has shown little clinical benefit, in spite of aberrant hyperactivation of mTOR in most solid tumors. Here, we discuss possible reasons for the reduced clinical efficacy of mTOR inhibition and highlight...

BRAF V600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF/MEK/EGFR co-targeting, we used a high throughput kinase activity mapping platform. We found that SRC kinases...

Purpose Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) and provide outcomes related to correlative biological factors associated with disease control. Patients and Methods This was a prospective, randomized, double-blind phase II t...

Genetic alterations and dysregulation of signaling pathways are indispensable for the initiation and progression of cancer. Understanding the genetic, molecular, and signaling diversities in cancer patients has driven a dynamic change in cancer therapy. Patients can select a suitable molecularly targeted therapy or immune checkpoint inhibitor based...

Work over the past several decades has identified that aberrations in the ErbB signaling pathways are key drivers of oncogenesis, and concurrent efforts to discover targetable vulnerabilities to counter this aberrant oncogenic signaling offer tremendous promise in treating a host of human cancers. These efforts have been centered primarily on EGFR...

Lymphangiogenesis is an essential physiological process but also a determining factor in vascular-related pathological conditions. Angiopoietin-2 (Ang2) plays an important role in lymphatic vascular development and function and its upregulation has been reported in several vascular-related diseases, including cancer. Given the established role of t...

Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employ tobacco-signature head and neck squamous cell carcinoma murine models in which we map tumor-draining lymphati...

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternat...

Trio is a large and highly conserved metazoan signaling scaffold that contains two Dbl family guanine nucleotide exchange factor (GEF) modules, TrioN and TrioC, selective for Rac and RhoA GTPases, respectively. The GEF activities of TrioN and TrioC are implicated in several cancers, especially uveal melanoma. However, little is known about how thes...

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer risk screening and treatment strategies. Using genotypes from over 8,000 European individuals in The Cancer Genome Atlas and 137 heritable tumor immune...

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, tobacco use, and abusive alcohol intake. Without truly effective targeted therapies, surgery and radiotherapy represent the prim...

Natural killer (NK) cells are a key effector in antitumor immunity. However, tumors often acquire resistance programs to escape NK cell-mediated immunosurveillance. Identifying targetable vulnerabilities that reinvigorate NK cell-driven antitumor immunity can enable new therapeutic strategies to improve NK cell-mediated anti-tumor activity. Previou...

Background Understanding the intricate signaling network involved in triple-negative breast cancer (TNBC) represents a challenge for developing novel therapeutic approaches. Here, we aim to provide novel mechanistic insights on the function of the S100A8/A9-RAGE system in TNBC. Methods TNM plot analyzer, Kaplan-Meier plotter, Meta-analysis, GEPIA2...

In this study we show that protein language models can encode structural and functional information of GPCR sequences that can be used to predict their signaling and functional repertoire. We used the ESM1b protein embeddings as features and the binding information known from publicly available studies to develop PRECOGx, a machine learning predict...

Head and neck squamous cell carcinoma (HNSCC) represents a highly prevalent and deadly malignancy worldwide. The prognosis for locoregionally advanced HNSCC has not appreciably improved over the past 30 years despite advances in surgical, radiation, and targeted therapies and less than 20% of HNSCC patients respond to recently approved immune check...

Purpose/Objective(s) PD-1 inhibition (PD1i) has demonstrated no benefit for locally advanced HNSCC, and emerging neoadjuvant PD1i window of opportunity yield promising but limited responses. Our preclinical work demonstrates that ablating tumor draining lymphatics compromises the response to immune-oncology (IO) therapy. In concert, a recently comp...

Purpose/Objective(s) Objective response rates to PD-1 blockade in human papillomavirus (HPV) mediated Head and Neck Squamous cell carcinoma (HNSCC) are low and resistance mechanisms are unclear. HPV oncogenes are known to modulate immune responses; however, the role that they play in limiting responses to PD-1 blockade is poorly understood. Here we...

Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hipp...

Immune checkpoint inhibition (ICI) with anti-CTLA-4 and anti-PD-1 has revolutionized oncology; however, response rates remain limited in most cancer types, highlighting the need for more effective immune oncology (IO) treatment strategies. Paradoxically, head and neck squamous cell carcinoma (HNSCC), which bears a mutational burden and immune infil...

Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Immunotherapies - principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity - offer the greatest promise for HNSCC treatment. Anti-P...

Despite the promise of immune checkpoint inhibition (ICI), therapeutic responses remain limited. This raises the possibility that standard of care treatments delivered in concert may compromise the tumor response. To address this, we employed tobacco-signature HNSCC murine models in which we mapped tumor-draining lymphatics and developed models for...

Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Immunotherapies ,principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity, offer the greatest promise for HNSCC treatment. Anti-PD-...

HRAS-MAPK and PI3K-AKT-mTOR are important oncogenic pathways in head and neck squamous cell carcinoma (HNSCC) and other squamous cell carcinomas (SCCs). HRAS is mutated in ~5% and overexpressed in approximately 30% of HNSCC patients, raising the possibility that some HRAS wild-type (WT) HNSCCs may also display a degree of dependence on HRAS. RAS pr...

The Hippo pathway is frequently dysregulated in cancer, leading to the unrestrained activity of its downstream targets, YAP/TAZ, and aberrant tumor growth. However, the precise mechanisms leading to YAP/TAZ activation in most cancers is still poorly understood. Analysis of large tissue collections revealed YAP activation in most head and neck squam...

Background Despite the proven efficacy of immune checkpoint inhibitor (ICI) therapy in the recurrent/metastatic setting for head and neck squamous cell carcinoma (HNSCC), clinical trials of ICI combined with curative-intent therapies have yielded equivocal results [1–4]. Collectively, this highlights gaps in our understanding of rational immune onc...

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which...

Mapping protein interactions driving cancer Cancer is a genetic disease, and much cancer research is focused on identifying carcinogenic mutations and determining how they relate to disease progression. Three papers demonstrate how mutations are processed through networks of protein interactions to promote cancer (see the Perspective by Cheng and J...

Mapping protein interactions driving cancer Cancer is a genetic disease, and much cancer research is focused on identifying carcinogenic mutations and determining how they relate to disease progression. Three papers demonstrate how mutations are processed through networks of protein interactions to promote cancer (see the Perspective by Cheng and J...

Many of the fundamental concepts of signal transduction and kinase activity are attributed to the discovery and crystallization of cAMP-dependent protein kinase, or protein kinase A. PKA is one of the best-studied kinases in human biology, with emphasis in biochemistry and biophysics, all the way to metabolism, hormone action, and gene expression r...

Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of h...

Background: The aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open label phase IIa clinical trial (NCT02581137) in individuals with oral premalignant lesions (OPL) to explore the potential of met...

p>Head and neck squamous cell carcinoma (HNSCC) ranks 6th in cancer incidence worldwide and has a five-year survival rate of only 63%. Despite advances in curative-intent therapies over the past three decades, rates of recurrence exceed 50% and long-term toxicities remain unacceptably morbid. Immunotherapies - principally immune checkpoint inhibito...

The RAS/RAF/MEK/ERK pathway is the most mutated oncogenic pathway in cancer, and RAS pathway mutations often present with an overall worse prognosis. Although RAF and MEK have been validated as anticancer targets and several BRAF and MEK inhibitors (MEKi) are FDA approved, acquired resistance develops in most patients. Preclinically, inhibition of...

p>Developing effective therapies to intervene in the tumor immune evasion process is a challenge further complicated by interindividual variability in tumor-host immunological interactions. Germline variation is a major component of interindividual variability usually studied by large-scale genome-wide association studies (GWAS) in the context of d...

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, and tobacco use and abusive alcohol intake. Recent revolutionary immunotherapy approaches have changed the landscape of treatmen...

TPS9588 Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. Currently there is no US FDA-approved treatment for metastatic uveal melanoma (MUM). Activating mutations in genes encoding alpha subunits of the heterotr...

Immune checkpoint blockade (ICB) therapy has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment, but <20% of patients achieve durable responses. Persistent activation of the PI3K/AKT/mTOR signaling circuitry represents a key oncogenic driver in HNSCC; however, the potential immunosuppressive effects of PI3K/AKT/mTOR inhibitors m...

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Approaches that intersect SNP modifiers of molecular phenotype, such as gene expression, with disease phenotypes ha...

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fib...

Senescent cells produce chronic inflammation that contributes to the diseases and debilities of aging. How this process is orchestrated in epithelial cells, the origin of human carcinomas, is poorly understood. We used human normal oral keratinocytes (NOKs) to elucidate senescence programs in a prototype primary mucosal epithelial cell that senesce...

Purpose: Uveal melanoma (UM) is the most common eye cancer in adults. Approximately 50% of UM patients develop metastatic UM (mUM) in the liver, even after successful treatment of the primary lesions. mUM is refractory to current chemo- and immune-therapies, and most mUM patients die within a year. UM is characterized by gain-of-function mutations...

Breast cancer represents the most common diagnosed malignancy and the main leading cause of tumor-related death among women worldwide. Therefore, several efforts have been made in order to identify valuable molecular biomarkers for the prognosis and prediction of therapeutic responses in breast tumor patients. In this context, emerging discoveries...

The DNA demethylating agent 5-aza-2′-deoxycytidine (DAC, decitabine) has anti-cancer therapeutic potential, but its clinical efficacy is hindered by DNA damage-related side effects and its use in solid tumours is debated. Here we describe how paracetamol augments the effects of DAC on cancer cell proliferation and differentiation, without enhancing...

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G protein coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs an...

Background Oncologically-sound standard of care therapy often indicates ablation of draining lymphatic basins to eradicate repositories of metastatic disease. However, emerging cancer immunotherapies often necessitate intact secondary lymphoid organs to achieve maximum effect. Therefore, multimodal immune-oncology (IO) therapeutic approaches introd...

A low-cost microfluidic microarray capable of lysing cells and quantifying proteins released after lysis was designed and 3D-printed. The array lyses cells on-chip in lysis buffer augmented with a 2s pulse of a sonic cell disruptor. Detection of desmoglein 3 (DSG3), a metastatic biomarker for head and neck squamous cell carcinoma (HNSCC), along wit...