TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations

NF-κB transcription factors, driven by the IRAK/IKK cascade, confer treatment resistance in pancreatic ductal adenocarcinoma (PDAC), a cancer characterized by near-universal KRAS mutation. Through reverse-phase protein array and RNA sequencing we discovered that IRAK4 also contributes substantially to MAPK activation in KRAS-mutant PDAC. IRAK4 ablation completely blocked RAS-induced transformation of human and murine cells. Mechanistically, expression of mutant KRAS stimulated an inflammatory, autocrine IL-1β signaling loop that activated IRAK4 and the MAPK pathway. Downstream of IRAK4, we uncovered TPL2 (also known as MAP3K8 or COT) as the essential kinase that propels both MAPK and NF-κB cascades. Inhibition of TPL2 blocked both MAPK and NF-κB signaling, and suppressed KRAS-mutant cell growth. To counter chemotherapy-induced genotoxic stress, PDAC cells upregulated TLR9, which activated prosurvival IRAK4/TPL2 signaling. Accordingly, a TPL2 inhibitor synergized with chemotherapy to curb PDAC growth in vivo. Finally, from TCGA we characterized 2 MAP3K8 point mutations that hyperactivate MAPK and NF-κB cascades by impeding TPL2 protein degradation. Cancer cell lines naturally harboring these MAP3K8 mutations are strikingly sensitive to TPL2 inhibition, underscoring the need to identify these potentially targetable mutations in patients. Overall, our study establishes TPL2 as a promising therapeutic target in RAS- and MAP3K8-mutant cancers and stron...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

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ann Pancreatic ductal adenocarcinoma (PDAC) represents 90% of pancreatic malignancies. In contrast to many other tumor entities, the prognosis of PDAC has not significantly improved during the past thirty years. Patients are often diagnosed too late, leading to an overall five-year survival rate below 10%. More dramatically, PDAC cases are on the rise and it is expected to become the second leading cause of death by cancer in western countries by 2030. Currently, the use of gemcitabine/nab-paclitaxel or FOLFIRINOX remains the standard chemotherapy treatment but still with limited efficiency. There is an urgent need for...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
At the time of diagnosis, only about 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have resectable disease. PDAC treatment necessitates a multidisciplinary approach, and adjuvant chemotherapy after upfront resection is an established means of preventing recurrence. Neoadjuvant chemotherapy (NAT), originally introduced to downstage tumor size, is nowadays more frequently used for selection of patients with favorable tumor biology and to control potential micrometastases. While NAT is routinely applied in locally advanced (LA) PDAC, there is increasing evidence demonstrating benefits of NAT in borderline resec...
Source: Pharmacology - Category: Drugs & Pharmacology Source Type: research
Authors: Hammel P, Zhang C, Matile J, Colle E, Hadj-Naceur I, Gagaille MP, Bouattour M, Cros J, de Mestier L, Lamuraglia M Abstract INTRODUCTION: Tumor control and survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) has improved with more effective polychemotherapies. The identification of novel therapeutic targets is strongly needed in order to propose maintenance therapies that improve quality of life while maintaining tumor control. AREAS COVERED: PDAC with mutations in homologous recombination repair genes such as BRCA are particularly sensitive to platinum agents. Recently, the pot...
Source: Expert Review of Anticancer Therapy - Category: Cancer & Oncology Tags: Expert Rev Anticancer Ther Source Type: research
This study compares the outcomes of neoadjuvant chemoradiation therapy with and without systemic chemotherapy in resectable and borderline resectable pancreatic cancers.Methods: This retrospective study evaluated patients with resectable and borderline resectable pancreatic adenocarcinoma who completed neoadjuvant chemoradiation therapy with and without systemic chemotherapy prior to surgical resection. 149 patients met inclusion criteria, with 75 having resectable cancer and 74 having borderline resectable cancer. Outcomes included recurrence free and overall survival rates at 6, 12, and 36 months.Results: In resectable p...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Abstract Desmoplasia is a major barrier to chemotherapy in several cancers, particularly pancreatic ductal adenocarcinoma and breast cancer. Tumors comprise cellular and noncellular components and chemoresistant cancer stem cells (CSCs) with established signaling pathways. In this review, we discuss drugs, such as pentoxifylline, aspirin, and metformin, that have been repurposed and investigated for their antidesmoplastic activity in combination with antitumor drugs. We also highlight less explored new small-molecule drugs, and gene and peptide-based therapeutics for the treatment of desmoplasia and to target CSCs...
Source: Drug Discovery Today - Category: Drugs & Pharmacology Authors: Tags: Drug Discov Today Source Type: research
Girijesh Kumar Patel, Josiah B Perry, Osama Abdul-Rahim, Arthur E Frankel, Daniel Cameron, William Taylor, Rodney P Rocconi, Laith Abushahin, Cindy Nelson, Ajay P Singh, Moh'd KhushmanJournal of Cancer Research and Therapeutics 2020 16(4):950-954 Despite recent advances in treatment with multidrug chemotherapy regimens, outcomes of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain very poor. Treatment with targeted therapies has shown marginal benefits due to intrinsic or acquired resistance. Actionable mutations, while detected infrequently in patients with PDAC, are becoming increasingly used in ...
Source: Journal of Cancer Research and Therapeutics - Category: Cancer & Oncology Authors: Source Type: research
This study aimed to retrospectively analyze the clinical outcomes of pancreatectomy with AR for pancreatic ductal adenocarcinoma. Patients with pancreatic ductal adenocarcinoma treated with pancreatectomy with AR at our institute between January 2000 and April 2017 were retrospectively reviewed. Operative outcome and survival were compared according to the presence of neoadjuvant chemotherapy. This study included 109 patients (38 underwent surgery after neoadjuvant chemotherapy, 71 underwent upfront surgery). The median hospital stay was 17 (interquartile range, 12–26.5) days. Clinically relevant postoperative panc...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Observational Study Source Type: research
Few studies have examined the role of stereotactic body radiation (SBRT) after multiagent chemotherapy (ChT) in pancreatic ductal adenocarcinoma (PDAC). This was a prospective study of SBRT after ChT for PDAC.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Source Type: research
Margin-negative (R0) resection is the only potentially curative treatment for patients (pts) with pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multi-agent chemotherapy alone (MAC) vs MAC followed by neoadjuvant radiotherapy (MAC+RT) may be used to improve resectability and potentially survivorship. However, the optimal preoperative regimen is unknown.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Source Type: research
Conditions:   Pancreatic Cancer;   Adenocarcinoma of the Pancreas;   Adenocarcinoma Interventions:   Drug: Motixafortide (BL-8040);   Drug: Cemiplimab;   Drug: Gemcitabine;   Drug: Nab paclitaxel Sponsors:   Gulam Manji;   Regeneron Pharmaceuticals;   BioLine Rx Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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