Gene expression and pathway bioinformatics analysis detect a potential predictive value of MAP3K8 in thyroid cancer progression

Thyroid cancer is the commonest endocrine malignancy. Mutation in the BRAF serine/threonine kinase is the most frequent genetic alteration in thyroid cancer. Target therapy for advanced and poorly differentiated thyroid carcinomas include BRAF pathway inhibitors. Here, we evaluated the role of MAP3K8 expression as a potential driver of resistance to BRAF inhibition in thyroid cancer. By analyzing Gene Expression Omnibus data repository, across all thyroid cancer histotypes, we found that MAP3K8 is up-regulated in poorly differentiated thyroid carcinomas and its expression is related to a stem cell like phenotype and a poorer prognosis and survival. Taken together these data unravel a novel mechanism for thyroid cancer progression and chemo-resistance and confirm previous results obtained in cultured thyroid cancer stem cellsComment: 5 page

PETAL: a python tool for deep analysis of biological pathways.

Abstract Summary Although several bioinformatics tools have been developed to examine signaling pathways, little attention has been given to ever long-distance crosstalk mechanisms. Here, we developed PETAL, a Python tool that automatically explores and detects the most relevant nodes within a KEGG pathway, scanning and performing an in-depth search. PETAL can contribute to discovering novel therapeutic targets or biomarkers that are potentially hidden and not considered in the network under study. Availabilityand implementation PETAL is a freely available open-source software. It runs on all platforms that support Python3. The user manual and source code are accessible from https://github.com/Pex2892/PETAL

Possible Contexts of Use for In Silico trials methodologies: a consensus- based review

The term In Silico Trial indicates the use of computer modelling and simulation to evaluate the safety and efficacy of a medical product, whether a drug, a medical device, a diagnostic product or an advanced therapy medicinal product. Predictive models are positioned as new methodologies for the development and the regulatory evaluation of medical products. New methodologies are qualified by regulators such as FDA and EMA through formal processes, where a first step is the definition of the Context of Use (CoU), which is a concise description of how the new methodology is intended to be used in the development and regulatory assessment process. As In Silico Trials are a disruptively innovative class of new methodologies, it is important to have a list of possible CoUs highlighting potential applications for the development of the relative regulatory science. This review paper presents the result of a consensus process that took place in the InSilicoWorld Community of Practice, an online forum for experts in in silico medicine. The experts involved identified 46 descriptions of possible CoUs which were organised into a candidate taxonomy of nine CoU categories. Examples of 31 CoUs were identified in the available literature; the remaining 15 should, for now, be considered speculative

IKBKE-DRIVEN TPL2 AND MEK1 PHOSPHORYLATIONS SUSTAIN CONSTITUTIVE ERK1/2 ACTIVATION IN TUMOR CELLS

peer reviewedIKBKE have been associated with numerous cancers. As a result, IKBKE have emerged as potential target for cancer therapy. Accumulating evidence support that IKBKE orchestrate tumor cell survival in cancers. Here we evaluated the possible link between IKBKE and ERK phosphorylation. The effects of IKBKE silencing on MAPK activation in tumor vs. normal cells were evaluated via WB and RT-PCR. Ectopically expressed IKBKE, TPL2 or MEK1 constructs were used to examine the possible interactions among them via co-IP. In vitro kinase assays were performed to understand nature of the observed interactions. In tumors, IKBKE regulates MEK/ERK constitutive activations in vitro and in vivo. IKBKE and TPL2 physically interact and this interaction leads to TPL2 phosphorylation. We describe here a novel regulatory link between IKBKE and constitutive ERK1/2 activation in tumor cells. This new circuitry may be relevant for tumor cell survival in various malignancies

Signaling Networks that Induce Melanomagenesis and Metastasis that can be Exploited for Therapeutic Benefit

Melanoma is the most lethal type of skin cancer and originates in melanocytes, cells that produce the pigment melanin. Five year survival rates are particularly high for this type of cancer if the tumor is diagnosed and treated early. However, survival rates decline significantly if the tumor is allowed to metastasize. Frequency of melanoma has risen over recent years, especially in young people. Much progress has been made in treating melanoma; however, tumor recurrence is frequently seen in patients after treatment has concluded. The leading genes that are found to be mutated in melanoma are v-Raf murine sarcoma viral oncogene homolog B1 (BRAF), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), phosphatase and tensin homolog deleted on chromosome ten (PTEN) and cyclin dependent kinase inhibitor 2A (CDKN2A) which belong to the MAPK (Mitogen-activated protein kinase/Extracellular signal-regulated kinases) pathway, the phosphoinositide 3\u27 kinase (PI3K)/AKT pathway or the INK4/ARF locus. Together, these two pathways and locus form a signaling network that work in tandem to promote cell proliferation, migration, invasion and metastasis. Recent breakthroughs in treating melanoma include the advent of BRAF inhibitors, but patients often experience tumor recurrence. Research conducted to understand acquired BRAF inhibitor resistance suggests that tumor regrowth is due to continued activation of the MAPK and PI3K/AKT pathways through BRAF independent routes. Therefore, new treatments, which can be personalized, are being developed that target multiple components of both of these pathways. The epigenetic causes of melanoma are vast and are just recently becoming clear

Advances and Novel Treatment Options in Metastatic Melanoma

The book presents several studies reporting advances on melanoma pathogenesis, diagnosis and therapy. It represents a milestone on the state of the art, updated at 2021, and also presents the current knowledge on the future developments in melanoma field

Targeting mutant KRAS in pancreatic cancer

The development of pharmacologic inhibitors of the KRAS oncoprotein, which is mutated in ~30% of all human cancers, has been at the forefront of drug discovery for the last three decades. Despite intensive efforts by the pharmaceutical industry, no effective anti-KRAS strategies have reached the cancer patient. While many approaches to achieve this are being pursued, arguably inhibition of mutant KRAS effector signaling is considered the most promising to block KRAS-driven cancer growth. The best-validated downstream effector of KRAS is a three-tiered protein kinase cascade, the Raf-MEK-ERK protein kinase cascade, where KRAS activates Raf, which then activates MEK, and MEK then activates ERK. Activated ERK then activates a complex spectrum of signaling events that then drive cancer growth. Unfortunately, inhibitors of the first two levels, targeting Raf or MEK, have proven ineffective in mutant KRAS cancers. The ineffectiveness of anti-Raf and –MEK therapies has been attributed to inhibitor-induced resistance mechanisms, where the majority cause reactivation of ERK signaling to bypass the action of these inhibitors. Our studies sought to determine whether pharmacological inhibition of the last step at ERK will be more efficacious than treatment with either MEK or Raf inhibitors in mutant KRAS cancers. In our studies, we first determined that pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines by inducing both cycle cell arrest and apoptosis. Interestingly, we found that concurrent PI3K inhibition, another well-established KRAS effector, modulated ERK inhibitor sensitivity by enhancing the apoptotic phenotype. Next, we employed a drug sensitivity screen to identify novel inhibitor combinations that enhanced ERK inhibitor sensitivity. We identified the PI3K-AKT-mTOR signaling cascade as a potent modulator of ERK inhibitor sensitivity, which was consistent with our previous finding where concurrent PI3K inhibition combination enhanced ERK inhibitor sensitivity. We unexpectedly found that long-term treatment of sensitive cell lines caused cellular senescence, a type of irreversible growth arrest, mediated in part by causing degradation of Myc and activation of the p16-RB tumor suppressor pathway. Next, we performed a novel genetic gain-of-function screen to identify mechanisms of acquired resistance to ERK inhibition. Interestingly, we identified, once again, the PI3K-AKT signaling cascade, as modulator of ERK inhibitor sensitivity. We also found p38 to be an important modulator or ERK inhibitor sensitivity. Finally, to investigate de novo resistance to ERK inhibition, we used a loss-of-function screen to identify kinases whose inhibition in combination with ERK inhibitor treatment resulted in sensitivity. Future studies will be needed to elucidate the mechanisms behind these modulators of pharmacological ERK inhibition. Collectively, our findings not only revealed distinct consequences of inhibiting this kinase cascade at the level of ERK, but identified inhibitor combinations that will be informative for potential clinical trials.Doctor of Philosoph

RSK4 targeting: A new therapeutic strategy against drug resistance and metastasis in non-small cell lung cancer

Lung cancer is the commonest cause of cancer death worldwide with a five-year survival rate of less than five percent for metastatic tumours. Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancer cases of which adenocarcinoma prevails. Patients almost invariably develop metastatic drug-resistant disease and this is responsible for our failure to provide curative therapy. Hence, a better understanding of the mechanisms underlying these biological processes is urgently required to improve clinical outcome. The p90 (90 kDa) Ribosomal Protein S6 Kinases (RSKs) are downstream effectors of the RAS/MAPK cascade. RSKs are highly conserved serine/threonine protein kinases implicated in diverse cellular processes, including cell survival, proliferation, migration and invasion. There are four human isoforms (RSK1-4), which are uniquely characterised by the presence of two non-identical N- and C-terminal kinase domains. RSK isoforms are 73%-80% identical at the protein level and this has been thought to suggest overlapping functions. However, through functional genomic kinome screens, we show that RSK4, contrary to RSK1, promotes both drug resistance and metastasis in lung cancer. RSK4 is overexpressed in the majority of NSCLC biopsies and this correlates with poor overall survival in lung adenocarcinoma patients. Genetic silencing of RSK4 sensitises lung cancer cells to chemotherapy and prevents their migration and invasiveness in vitro and in vivo. This is associated with downregulation of the anti-apoptotic proteins c-IAP1 and c-IAP2, and induction of mesenchymal-epithelial transition (MET), respectively. A small-molecule inhibitor screen identified several floxacins as potent allosteric inhibitors of RSK4 activation. Trovafloxacin reproduced all biological and molecular effects of RSK4 silencing in vitro and in vivo and it is predicted to bind a novel allosteric site as revealed by our RSK4 N-terminal kinase domain crystal structure and mathematical Markov Transient Analysis. Taken together, our data implicate RSK4 as a promising novel therapeutic target in lung cancer.Open Acces