Proposed Modification of the 8th Edition of the AJCC Staging System for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The aim of this study was to improve the 8th edition (8th) of the American Joint Committee on Cancer (AJCC) staging system for pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: The new 8th AJCC staging system for PDAC was released in October, 2016, and will be applied in clinical practice in 2018. METHODS: Two large cohorts were included in this analysis. One consisted of 45,856 PDAC patients in the Surveillance, Epidemiology, and End Results (SEER) database (2004-2014), and the other consisted of 3166 PDAC patients in the Fudan University Shanghai Cancer Center (FUSCC) database (2005-2015). RESULTS: Using the 8th AJCC staging system, the median overall survival of the patients in the same stage varied widely among the different substages. We proposed a modified staging system based on median OS in which we maintained the T, N, and M definitions, but regrouped the substages. In the SEER cohort, the concordance index was higher for local disease with the modified staging system [0.637; 95% confidence interval (CI) 0.631-0.642] than with the 8th AJCC staging system (0.620, 95% CI 0.615-0.626). Similar findings were also observed in the FUSCC cohort. In addition, we verified the reliability of the modified staging system in an analysis of patients with different examined lymph node counts (≥15 or 1-14). CONCLUSIONS: The modified 8th AJCC staging system for PDAC proposed in this study provides improvements and may be evaluated for potential adoption in the next edition.

Current status and dilemma of second-line treatment in advanced pancreatic cancer: is there a silver lining?

Pancreatic cancer remains one of the most lethal malignant diseases worldwide. The majority of patients present with advanced disease and, therefore, need palliative chemotherapy. Some chemotherapeutic regimens have been well established as first-line therapies and have been shown to increase survival; however, almost all patients with advanced pancreatic cancer will experience disease progression after first-line therapy. Nevertheless, many patients who retain good performance status after initial treatment remain good candidates for additional therapy. Historically, few studies have assessed second-line therapy, with most reports representing small phase II trials with variable findings; however, clinical research for second-line treatment has increased in the past decade, and several randomized controlled trials using different regimens have been published. The current literature shows varying results on treatment efficacy and tolerability. Thus, we reviewed the published data on the use of chemotherapy in the second-line setting for the treatment of advanced pancreatic cancer.

Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3ß/Snail signaling.

The devastating prognosis of pancreatic ductal adenocarcinoma (PDAC) is partially attributed to chemotherapy resistance. Glutathione peroxidase-1 (GPx1) plays various roles in the development and progression of multiple tumors, with the exception of pancreatic cancer. Here, we tentatively explored the role of GPx1 in the malignant biological behavior and gemcitabine (GEM) resistance of PDAC. GPx1 levels were detected using tissue microarrays and were negatively correlated with the overall survival of patients with PDAC. GPx1 silencing induced a mesenchymal transition phenotype and increased GEM resistance in vitro and in vivo. Additionally, the activation of reactive oxygen species (ROS)-mediated Akt/glycogen synthase kinase 3ß (GSK3ß)/Snail signaling was involved in this process, as determined by RNA sequencing. Moreover, low GPx1 expression correlated with a worse survival rate in patients with PDAC who received GEM adjuvant chemotherapy, whereas this correlation was not detected in patients receiving fluoropyrimidine. Based on our results, GPx1 inhibits the epithelial-mesenchymal transition (EMT) and chemoresistance by regulating the Akt/GSK3ß/Snail signaling axis in PDAC. Furthermore, GPx1 may be a potential predictive biomarker in GEM-treated PDAC patients.

MiR-29a, targeting caveolin 2 expression, is responsible for limitation of pancreatic cancer metastasis in patients with normal level of serum CA125.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal tumors, with an overall 5-year survival rate less than 8%. The dismal prognosis is mainly due to aggressive potential for metastasis. Hence, there is an urgent need for a better understanding of the molecular mechanisms underlying pancreatic cancer invasion and metastasis to improve the unfavorable overall survival (OS) of PDAC patients. In this study, we identified microRNA-29a (miR-29a) as an important tumor suppressor, which was downregulated in PDAC tissues. Moreover, miR-29a counteracted MUC16-mediated migration and invasion. In the pancreatic cancer cells, MUC16 upregulated c-Myc expression, which enhanced c-Myc binding to E-box in the miR-29a promoter and inhibited miR-29a transcription. Thus, miR-29a was negatively correlated with both MUC16 expression and serum CA125 levels. Furthermore, caveolin 2 (CAV2) was demonstrated to be the target of miR-29a by bioinformatics and luciferase reporter assays, and high CAV2 expression was responsible for a poor prognosis, especially in the subgroup with normal CA125 levels. Thus, the present study explains why high levels of serum CA125 are correlated with PDAC metastasis, highlighting the predictive value of this marker in PDAC patients.

TCF7L2 positively regulates aerobic glycolysis via the EGLN2/HIF-1α axis and indicates prognosis in pancreatic cancer.

Patients with pancreatic ductal adenocarcinoma have much worse prognoses, and much effort has been directed toward understanding the molecular biological aspects of this disease. Accumulated evidence suggests that constitutive activation of the Wnt/ß-catenin signalling contributes to the oncogenesis and progression of pancreatic cancer. Transcription factor 7-like2/transcription factor 4 (TCF7L2/TCF4), a ß-catenin transcriptional partner, plays a vital role in the Wnt/ß-catenin signalling pathway. In the present study, we investigated the clinicopathological significance of TCF7L2 in pancreatic cancer. Our results demonstrated that patients with higher TCF7L2 expression had worse prognosis. Our in vitro studies demonstrated that TCF7L2 positively regulated aerobic glycolysis by suppressing Egl-9 family hypoxia inducible factor 2 (EGLN2), leading to upregulation of hypoxia inducible factor 1 alpha subunit (HIF-1α). The impact of TCF7L2 on aerobic glycolysis was further confirmed in vivo by assessing 18FDG uptake in pancreatic cancer patients and in a subcutaneous xenograft mouse model. In summary, we identified novel predictive markers for prognosis and suggest a previously unrecognized role for TCF7L2 in control of aerobic glycolysis in pancreatic cancer.

Mismatch repair status as a beneficial predictor of fluorouracil-based adjuvant chemotherapy for pancreatic cancer.

BACKGROUND: Prior studies have indicated that patients with colorectal cancer with deficient mismatch repair have particular clinicopathologic features that distinguish them from patients with tumors with proficient mismatch repair. However, the effect of the mismatch repair status on outcomes after adjuvant chemotherapy for pancreatic cancer is still unknown. METHODS: Pancreatic cancer patients who underwent R0 resection between January 2013 and December 2015 at Fudan University Shanghai Cancer Center were included in this study. Mismatch repair status was determined by immunohistochemistry of mismatch repair proteins. Prognostic factors for deficient mismatch repair and proficient mismatch repair tumors were analyzed using Cox models. RESULTS: In total, 442 of 590 patients met the inclusion criteria, and their mismatch repair status was determined; the study group consisted of 75 patients with deficient mismatch repair and 367 patients with proficient mismatch repair. Among the 147 patients who underwent surgery alone, patients with deficient mismatch repair tumors had a better overall survival than patients with proficient mismatch repair tumors (hazard ratio = 0.555 [95% confidence interval 0.331-0.931]; P = .026). Compared with patients who underwent surgery, 161 patients who received gemcitabine-based adjuvant chemotherapy had improvements in both disease-free survival and overall survival, regardless of mismatch repair status. However, 5-fluorouracil-based adjuvant chemotherapy yielded a favorable disease-free survival in the proficient mismatch repair group but conferred no survival advantage in the deficient mismatch repair group (hazard ratio = 0.930 [95% confidence interval 0.497-1.743]; P = .821). CONCLUSION: Mismatch repair status in pancreatic cancer patients is not only a prognostic indicator but also a potential guiding factor for the use of 5-fluorouracil-based adjuvant chemotherapy.

Do anti-stroma therapies improve extrinsic resistance to increase the efficacy of gemcitabine in pancreatic cancer?

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies, with approximately 20-30% of PDAC patients receiving the surgical resection with curative intent. Although many studies have focused on finding ideal "drug chaperones" that facilitate and/or potentiate the effects of gemcitabine (GEM) in pancreatic cancer, a significant benefit in overall survival could not be demonstrated for any of these combination therapies in PDAC. Given that pancreatic cancer is characterized by desmoplasia and the dual biological roles of stroma in pancreatic cancer, we reassess the importance of stroma in GEM-based therapeutic approaches in light of current findings. This review is focused on understanding the role of stromal components in the extrinsic resistance to GEM and whether anti-stroma therapies have a positive effect on the GEM delivery. This work contributes to the development of novel and promising combination GEM-based regimens that have achieved significant survival benefits for the patients with pancreatic cancer.

Diagnostic Accuracy of a CA125-Based Biomarker Panel in Patients with Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Background: Increasing evidence from recent studies has revealed the association of CA125 with the diagnosis of pancreatic cancer, but inconsistent findings have been reported. We aimed to evaluate the diagnostic value of a serum CA125-based diagnostic panel in predicting malignant pancreatic cancer. Materials and Methods: We searched EMBASE, MEDLINE and Web of Science for relevant articles from inception to October 2016. Methodological quality was evaluated using the Quality Assessment of Comparative Diagnostic Accuracy Studies (QUADAS-2) checklist. The performance characteristics were pooled using random-effects models. The statistical analysis was performed using Meta-Disc 1.4 and Stata Version 12.0 software. Results: A total of 1235 participants pooled from 8 eligible studies were included in the meta-analysis to evaluate the accuracy of tumor predictors for the diagnosis of pancreatic cancer. The pooling accuracy analysis of CA125 alone indicated that the pooled sensitivity was 0.59 (95% CI: 0.54-0.62) and the specificity was 0.78 (95% CI: 0.75-0.82), whereas the serum CA125-based diagnostic panel had a pooled sensitivity of 0.47 (95% CI 0.47-0.51) and a specificity of 0.88 (95% CI 0.86-0.90). Furthermore, the AUC and Q-value of the CA125-based diagnostic panel were 0.89 and 0.82, respectively, which indicated that the CA125-based panel is superior to CA125 or CA19-9 alone in diagnosing pancreatic cancer. No obvious publication bias was found. Conclusions: In summary, a CA125-based diagnostic panel is better at diagnosing pancreatic cancer than a test using CA125 or CA19-9 alone. Further studies should be performed to confirm our conclusion.

Diagnostic and prognostic value of carcinoembryonic antigen in pancreatic cancer: a systematic review and meta-analysis.

BACKGROUND: Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers and is increased in 30%-60% of patients with pancreatic cancer. Although carbohydrate antigen 19-9 (CA19-9) is the most important serum biomarker in pancreatic cancer, the diagnostic and prognostic value of CEA is gradually being recognized. MATERIALS AND METHODS: The MEDLINE, EMBASE, and Web of Science databases were searched for related literature published until January 2017. Diagnostic accuracy variables were pooled using the Meta-Disc software. The pooled hazard ratios (HRs) for prognostic data were calculated and analyzed using Stata software. RESULTS: A total of 3,650 participants enrolled in 19 studies met our inclusion criteria. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of a CEA-based panel were 0.45 (95% confidence interval [CI], 0.41-0.50), 0.89 (95% CI, 0.86-0.91), 5.39 (95% CI, 3.16-9.18), and 0.55 (95% CI, 0.41-0.72), respectively. The area under the curve (AUC, 0.90) and Q-value (0.84) of the CEA-based panel indicated a significantly higher diagnostic accuracy compared with CEA or CA19-9 alone. Moreover, there was also a significant association between high levels of CEA and worse overall survival (HR, 1.43; 95% CI, 1.31-1.56). CONCLUSION: Our meta-analysis indicated that elevated serum CEA level, as a vital supplementary to CA19-9, can play an important role in the clinical diagnosis of pancreatic cancer patients and predict poor prognosis.

FBW7 increases the chemosensitivity of pancreatic cancer cells to gemcitabine through upregulation of ENT1.

F-box and WD repeat domain-containing 7 (FBW7) has been characterized as a tumor suppressor, and its mutation or decreased expression has been observed in many types of human cancers. Our recent studies have uncovered that in pancreatic cancer, the KRAS mutation decreased FBW7 expression through phosphorylation and subsequent ubiquitination. Moreover, FBW7 inhibited aerobic glycolysis in pancreatic cancer via induction of thioredoxin-interacting protein (TXNIP), a mitochondrial localized tumor suppressor. The roles of FBW7 in anti-apoptosis and drug resistance via proteosomal degradation of myeloid cell leukemia-1 (MCL-1), which is an anti-apoptotic factor have been reported. However, the role of FBW7 in the chemotherapeutic resistance of pancreatic cancer to gemcitabine has seldom been reported. In the present study, we demonstrated that overexpression of FBW7 in pancreatic cancer cells rendered increased sensitivity to gemcitabine. Mechanistically, FBW7 promoted gemcitabine sensitivity via upregulation of equilibrative nucleoside transporter 1 (ENT1) at the protein level rather than the transcriptional level. In depth analysis demonstrated that the ENT1 protein level could be increased by lysosome inhibition. Taken together, our results demonstrated that FBW7 could be a target for improving the therapeutic efficacy of gemcitabine by induction of ENT1.

A new facet of NDRG1 in pancreatic ductal adenocarcinoma: Suppression of glycolytic metabolism.

N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1α level. Moreover, NDRG1 has a unique role in modulating cancer metabolism of pancreatic ductal adenocarcinoma (PDAC). The mechanism accounting for NDRG1 in modulating aerobic glycolysis, at least partly, relied on its regulation of glycolysis genes including GLUT1, HK2, LDHA and PDK1. Additionally, NDRG1 is shown to suppress the activity of HIF1α, which is responsible for regulation of glycolysis enzymes. The current study is the first to elucidate a unique facet of the potent tumor/metastasis suppressor NDRG1 in the regulation of PDAC glycolysis, leading to important insights into the mechanism by which NDRG1 exert inhibitory function in PDAC.

Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with the 5-year survival rate less than 6%. Previous results indicated that serum levels of CA125 (encoded by MUC16) could be used to predict which groups of pancreatic cancer patients may benefit from surgery. However, the underlying mechanism remains elusive. Herein, using the Cancer Genome Atlas and clinicopathologic data obtained from our center, we demonstrate that high CA125 serum levels and expression levels of MUC16 are predictive of poor prognosis. MUC16 is also validated as a downstream target of KRAS, and their expression strongly correlated with each other in vitro and in vivo Mechanistically, the KRAS/ERK axis induced upregulation of MUC16 and shedding of CA125 via its effector c-Myc in SW1990 and PANC-1 pancreatic cancer cells. Notably, proto-oncogene c-Myc could bind to the promoter of MUC16 and transcriptionally activate its expression. Taken together, these data establish CA125 as a prognostic marker for pancreatic cancer, and mechanistic studies uncovered the KRAS/c-Myc axis as a driving factor for upregulation of MUC16. IMPLICATIONS: The current study uncovers the contribution of oncogenic KRAS to serum marker CA125 production through a mechanism that involves the ERK/c-Myc axis. Mol Cancer Res; 15(2); 201-12. ©2016 AACR.

Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going.

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.

ARF6, induced by mutant Kras, promotes proliferation and Warburg effect in pancreatic cancer.

Though significant progress has been made in the availability of diagnostic techniques and treatment strategies, pancreatic cancer remains a disease of high mortality rates. Therefore, there is an urgent need for a better understanding of the molecular mechanisms that governs the oncogenesis and metastasis process of pancreatic cancer. In our study, by using the Cancer Genome Atlas (TCGA) dataset analysis, we demonstrated that the small guanosine triphosphatase (GTPase) ADP-ribosylation factor 6 (ARF6) serves as a biomarker for predicting prognosis of pancreatic cancer. In vitro studies demonstrated that silencing ARF6 expression reduced cell proliferation and attenuated the Warburg effect. Moreover, we observed that ARF6 was a downstream target of Kras/ERK signaling pathway, and the strong correlation of expression between Kras and ARF6 in the TCGA dataset further confirmed this observation. Taken together, our novel findings suggest ARF6, a target of mutant Kras, may promote pancreatic cancer development by enhancing the Warburg effect.

Metabolic plasticity in heterogeneous pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignant neoplasms. The recognized hallmarks of PDA are regarded to be downstream events of metabolic reprogramming. Because PDA is a heterogeneous disease that is influenced by genetic polymorphisms and changes in the microenvironment, metabolic plasticity is a novel feature of PDA. As intrinsic factors for metabolic plasticity, K-ras activation and mutations in other tumor suppressor genes induce abnormal mitochondrial metabolism and enhance glycolysis, with alterations in glutamine and lipid metabolism. As extrinsic factors, the acidic and oxygen/nutrient-deprived microenvironment also induces cancer cells to reprogram their metabolic pathway and hijack stromal cells (mainly cancer-associated fibroblasts and immunocytes) to communicate, thereby adapting to metabolic stress. Therefore, a better understanding of the metabolic features of PDA will contribute to the development of novel diagnostic and therapeutic strategies.

Energy sources identify metabolic phenotypes in pancreatic cancer.

Metabolic reprogramming is one of the emerging hallmarks of cancers. As a highly malignant tumor, pancreatic ductal adenocarcinoma (PDA) is not only a metabolic disease but also a heterogeneous disease. Heterogeneity induces PDA dependence on distinct nutritive substrates, thereby inducing different metabolic phenotypes. We stratified PDA into four phenotypes with distinct types of energy metabolism, including a Warburg phenotype, a reverse Warburg phenotype, a glutaminolysis phenotype, and a lipid-dependent phenotype. The four phenotypes possess distinct metabolic features and reprogram their metabolic pathways to adapt to stress. The metabolic type present in PDA should prompt differential imaging and serologic metabolite detection for diagnosis and prognosis. The targeting of an individual metabolic phenotype with corresponding metabolic inhibitors is considered a promising therapeutic approach and, in combination with chemotherapy, is expected to be a novel strategy for PDA treatment.

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer.

PURPOSE: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy. EXPERIMENTAL DESIGN: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo Finally, gene expression profiling was performed to identify core signaling pathways. RESULTS: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose ((18)F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner. CONCLUSIONS: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950-60. ©2016 AACR.

ALDOA functions as an oncogene in the highly metastatic pancreatic cancer.

Pancreatic cancer is an aggressive and devastating disease that is characterized by uncontrolled progression, invasiveness and resistance to conventional treatment. In the past decades, much effort has been given to cancer genetics and pathological classification of this disease. Our previous study has uncovered a subgroup of patients with poor outcome, which is characterized by serum signature of CEA(+)/CA125(+)/CA19-9 ≥ 1000 U/mL; however, the underlying biology mechanism remains poorly understood. By using high-throughput screening analysis, we analyzed gene expression signature in highly malignant patients with serum markers of CEA(+)/CA125(+)/CA19-9 ≥ 1000 U/mL. Multiple differentially expressed genes were identified, many of which were closely related with cancer metabolic changes. Treatment of pancreatic cancer cell lines PANC-1 with transforming growth factor-ß (TGF-ß), which was commonly used to induce metastasis, has uncovered that the glycolytic process and antioxidant response was up-regulated upon TGF-ß stimulation. These results were consistent with the high-throughput screening analysis. Subsequent analysis indicated that among glycolytic genes, aldolase A (ALDOA) increased the most significantly upon TGF-ß treatment. Further in vitro and in vivo results demonstrated that ALDOA was associated with proliferation and metastasis of pancreatic cancer cells. Moreover, ALDOA predicted poor prognosis of pancreatic cancer, partially due to its role in E-cadherin expression regulation, and the results were further validated by analysis of the correlation between ALDOA and E-cadherin expression in pancreatic cancer tissue samples. Mechanistically, the role of ALDOA in pancreatic cancer might attribute to its regulation of c-Myc, HIF1α and NRF2 (Nuclear Factor, Erythroid 2-Like 2), which were key regulators of glycolysis and antioxidant response control.

New insights into perineural invasion of pancreatic cancer: More than pain.

Pancreatic cancer is one of the most malignant human tumors. Perineural invasion, whereby a cancer cell invades the perineural spaces surrounding nerves, is acknowledged as a gradual contributor to cancer aggressiveness. Furthermore, perineural invasion is considered one of the root causes of the recurrence and metastasis observed after pancreatic resection, and it is also an independent predictor of prognosis. Advanced research has demonstrated that the neural microenvironment is closely associated with perineural invasion in pancreatic cancer. Therapy targeting the molecular mechanism of perineural invasion may enable the durable clinical treatment of this formidable disease. This review provides an overview of the present status of perineural invasion, the relevant molecular mechanisms of perineural invasion, pain and hyperglycemia associated with perineural invasion in pancreatic cancer, and the targeted therapeutics based on these studies.

ERK kinase phosphorylates and destabilizes the tumor suppressor FBW7 in pancreatic cancer.

F-box and WD repeat domain-containing 7 (FBW7) is the substrate recognition component of the Skp1-Cul1-F-box (SCF) ubiquitin ligase complex and functions as a major tumor suppressor by targeting various oncoproteins for degradation. Genomic deletion or mutation of FBW7 has frequently been identified in many human cancers but not in pancreatic ductal adenocarcinoma. Thus it is important to know how the tumor suppressive function of FBW7 is impaired in pancreatic cancer. In this study, we first observed that low FBW7 expression correlated significantly with ERK activation in pancreatic cancer clinical samples, primarily due to KRAS mutations in pancreatic cancer. We further showed that ERK directly interacted with FBW7 and phosphorylated FBW7 at Thr205, which sequentially promoted FBW7 ubiquitination and proteasomal degradation. Furthermore, the phospho-deficient T205A FBW7 mutant is resistant to ERK activation and could significantly suppress pancreatic cancer cell proliferation and tumorigenesis. These results collectively demonstrate how the oncogenic KRAS mutation inhibits the tumor suppressor FBW7, thus revealing an important function of KRAS mutations in promoting pancreatic cancer progression.