• KRAS mutation
• cancer
• immunotherapy
• oncogene
• tumor microenvironment

• ABC drug transporters
• anti-EGFR
• anti-MET
• metastatic colorectal cancer
• resistance
• tyrosine kinase inhibitors

• R01 CA148706 NCI NIH HHS
• R01 CA240447 NCI NIH HHS

• colorectal cancer
• insulin receptor substrate
• insulin-like growth factor family
• meta-analysis
• polymorphism

• Colorectal cancer
• Obesity
• Phenotypes

• Adult
• Aged
• Body Mass Index
• Body Weight
• Cohort Studies
• Colorectal Neoplasms/etiology
• Female
• Humans
• Ideal Body Weight
• Male
• Metabolic Diseases/complications
• Metabolic Diseases/metabolism
• Middle Aged
• Obesity/complications
• Obesity/metabolism
• Obesity, Metabolically Benign/complications
• Obesity, Metabolically Benign/metabolism
• Odds Ratio
• Phenotype
• Risk Assessment
• Risk Factors

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

• EGFR
• cetuximab
• drug resistance
• metastatic colorectal cancer
• panitumumab

• IGF1R
• NHERF1
• apoptosis
• cell survival
• metastasis

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.

• HDAC
• gemcitabine
• histone deacetylase
• histone deacetylase inhibitor
• pancreatic ductal adenocarcinoma

• Direct inhibition
• downstream effectors
• drug target sites
• oncogenic KRAS
• signal transduction
• small GTPases
• targeting synthetic, lethal interactions
• therapeutic strategies

• Colorectal neoplasia
• Metabolic abnormalities
• Obesity

• A-kinase anchoring protein (AKAP)
• IGF1R
• Smad3
• X-linked inhibitor of apoptosis protein (XIAP)
• apoptosis
• colon cancer
• ezrin
• metastasis
• survivin
• transforming growth factor beta (TGF-β)

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is effective for patients with RAS wild type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients are sensitive to anti-EGFR therapy and even the best cases finally become refractory to this therapy. It has become apparent that the RAS mutations correlate with resistance to anti-EGFR therapy. However, these resistance mechanisms only account for nearly 35% to 50% of nonresponsive patients, suggesting that there might be additional mechanisms. In fact, several novel pathways leading to escape from anti-EGFR therapy have been reported in recent years. In this review, we provide an overview of known and novel mechanisms that contribute to both primary and acquired anti-EGFR therapy resistance, and enlist possible treatment strategies to overcome or reverse this resistance.

• acquired resistance
• colorectal cancer
• epidermal growth factor receptor
• primary resistance
• targeted drug

• Apoptosis
• DNA damage
• EGFR
• Heterodimerisation
• IGF1R
• Radiochemotherapy

• Adenocarcinoma/epidemiology
• Adenoma/epidemiology
• Adult
• Aged
• Colonoscopy
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/epidemiology
• Cross-Sectional Studies
• Female
• Humans
• Insulin Resistance
• Male
• Metabolic Syndrome/epidemiology
• Middle Aged
• Obesity/epidemiology
• Obesity, Metabolically Benign/epidemiology
• Odds Ratio
• Regression Analysis
• Republic of Korea/epidemiology
• Retrospective Studies
• Risk Factors

• IGF
• IRS
• RAS
• SNP
• metastatic colorectal cancer

• Adaptor Proteins, Signal Transducing/metabolism
• Apoptosis/genetics
• Cell Line, Tumor
• Cell Proliferation/genetics
• Colon/metabolism
• Colon/pathology
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Colonic Neoplasms/pathology
• Cyclin D1/metabolism
• Down-Regulation/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Insulin Receptor Substrate Proteins/antagonists & inhibitors
• Phosphorylation/genetics
• Signal Transduction/genetics
• Smad3 Protein/metabolism
• Transforming Growth Factor beta/metabolism
• X-Linked Inhibitor of Apoptosis Protein/metabolism

• R01 DK060632 NIDDK NIH HHS
• P30 GM106397 NIGMS NIH HHS
• R01 CA140988 NCI NIH HHS
• R37 CA038173 NCI NIH HHS
• R01 CA054807 NCI NIH HHS
• R01 CA038173 NCI NIH HHS
• P30 CA036727 NCI NIH HHS
• National Institutes of Health

The gradual elucidation of the underlying biology of colorectal cancer has provided new insights and therapeutic options for patients with metastatic disease which are selected according to predictive biomarkers. This precision medicine paradigm, however, is incomplete since not all eligible patients respond to these agents and prognostic stratification is largely based on clinicopathologic variants. Importantly, no robust data exist to help properly select patients with localized disease at high risk for recurrence and most likely to benefit from adjuvant chemotherapy. There is a rapidly expanding body of literature regarding the role of the qualitative and quantitative analysis of circulating free DNA in various neoplasms, which consistently outperforms traditional tumor markers both as a predictive and as a prognostic marker. Several lines of evidence suggest that circulating free DNA may exhibit a complementary role to existing modalities for the early diagnosis of colorectal cancer, the selection of patients for adjuvant chemotherapy, for the follow-up of treated patients, for the selection of treatment for advanced disease and the assessment of response and for determining the prognosis of patients. These data, which are reviewed here, illustrate the important role that circulating biomarkers may soon have at the daily clinical practice.

• Cell-free DNA
• Circulating tumor DNA
• Colorectal cancer
• Biomarker
• KRAS

The insulin/insulin-like growth factor (IGF) system is a major determinant in the pathogenesis and progression of colorectal cancer (CRC). Indeed, several components of this signaling network, including insulin, IGF-1, IGF-2, the IGF-binding proteins, the insulin receptor (IR), the IGF-1 receptor (IGF-1R), and IR substrate proteins 1 and 2 contribute to the transformation of normal colon epithelial cells. Moreover, the insulin/IGF system is also implicated in the development of resistance to both chemotherapeutic drugs and epidermal growth factor receptor targeted agents. The identification of hybrid receptors comprising both the IR and IGF-1R adds further complexity to this signaling network. Thus, a comprehensive understanding of the biological functions performed by each component of the insulin/IGF system is required to design successful drugs for the treatment of CRC patients.

• IGF
• IGF receptor
• colorectal cancer
• insulin
• insulin receptor
• insulin/IGF signaling
• therapy resistance

• 2D-DIGE proteomics
• Cell survival signaling
• Colorectal cancer metastasis
• Ezrin
• IGF1R signaling
• XIAP and survivin

• Animals
• Antibodies, Monoclonal/pharmacology
• Antibodies, Monoclonal, Humanized
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Survival
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Cytoskeletal Proteins/antagonists & inhibitors
• Cytoskeletal Proteins/genetics
• Cytoskeletal Proteins/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Inhibitor of Apoptosis Proteins/metabolism
• Liver Neoplasms/metabolism
• Liver Neoplasms/secondary
• Mice
• Mice, Nude
• Phosphorylation
• RNA Interference
• RNA, Small Interfering/metabolism
• Receptor, IGF Type 1/metabolism
• Signal Transduction/drug effects
• Survivin
• Transplantation, Heterologous
• X-Linked Inhibitor of Apoptosis Protein/metabolism

• R01 CA038173 NCI NIH HHS
• R01 CA034432 NCI NIH HHS
• R01 CA072001 NCI NIH HHS
• R37 CA038173 NCI NIH HHS
• R01 CA054807 NCI NIH HHS

The dismal outcome of malignant peripheral nerve sheath tumor (MPNST) highlights the necessity of finding new therapeutic methods to benefit patients with this aggressive sarcoma. Our purpose was to investigate epidermal growth factor receptor (EGFR) as a potential therapeutic target in MPNSTs.

We performed a microarray based-comparative genomic hybridization (aCGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center (MD Anderson) and 26 patients from Tianjin Medical University Cancer Institute & Hospital (TMUCIH). Fluorescence in situ hybridization (FISH) method was used to validate the gene amplification detected by aCGH analysis. Another independent cohort of 56 formalin fixed paraffin embedded (FFPE) MPNST samples was obtained to explore EGFR protein expression by immunohistochemical analysis. Cell biology detection and validation were performed on human MPNST cell lines ST88-14 and STS26T.

aCGH and pathway analysis of the 51 MPNSTs identified significant gene amplification events in EGFR pathway, including frequent amplifications of EGFR gene itself, which was subsequently validated by FISH assay. High expression of EGFR protein was associated with poor disease-free and overall survival of human MPNST patients. In human MPNST cell lines ST88-14 and STS26T, inhibition of EGFR by siRNA or Gefitinib led to decreased cell proliferation, migration, and invasion accompanied by attenuation of PI3K/AKT and MAPK pathways.

These results suggest that EGFR is a potential therapeutic target for MPNST.

• Resistance
• anti-epidermal growth factor receptor (anti-EGFR)
• colorectal cancer

• biomarker
• colorectal cancer
• personalized medicine
• targeted therapy

• cancer
• drug combination
• inhibitor
• insulin receptor
• insulin-like growth factor-1 receptor

Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient's specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis.

• KRAS mutation
• KRAS testing methods
• personalized medicine

• igf-1r inhibitors
• monoclonal antibodies
• tyrosine kinase inhibitors
• predictive biomarker

• Adrenocortical Carcinoma/drug therapy
• Adrenocortical Carcinoma/metabolism
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Female
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Receptor, IGF Type 1/antagonists & inhibitors
• Receptor, IGF Type 1/metabolism
• Sarcoma/drug therapy
• Sarcoma/metabolism

TGFβ signaling has typically been associated with suppression of tumor initiation while the role it plays in metastasis is generally associated with progression of malignancy. However, we present evidence here for an anti-metastatic role of TGFβ signaling.

To test the importance of TGFβ signaling to cell survival and metastasis we compared human colon carcinoma cell lines that are either non-tumorigenic with TGFβ response (FET), or tumorigenic with TGFβ response (FETα) or tumorigenic with abrogated TGFβ response via introduction of dominant negative TGFβRII (FETα/DN) and their ability to metastasize. Metastatic competency was assessed by orthotopic transplantation. Metastatic colony formation was assessed histologically and by imaging.

Abrogation of TGFβ signaling through introduction of a dominant negative TGFβ receptor II (TGFβRII) in non-metastatic FETα human colon cancer cells permits metastasis to distal organs, but importantly does not reduce invasive behavior at the primary site. Loss of TGFβ signaling in FETα-DN cells generated enhanced cell survival capabilities in response to cellular stress in vitro. We show that enhanced cellular survival is associated with increased AKT phosphorylation and cytoplasmic expression of inhibitor of apoptosis (IAP) family members (survivin and XIAP) that elicit a cytoprotective effect through inhibition of caspases in response to stress. To confirm that TGFβ signaling is a metastasis suppressor, we rescued TGFβ signaling in CBS metastatic colon cancer cells that had lost TGFβ receptor expression due to epigenetic repression. Restoration of TGFβ signaling resulted in the inhibition of metastatic colony formation in distal organs by these cells. These results indicate that TGFβ signaling has an important role in the suppression of metastatic potential in tumors that have already progressed to the stage of an invasive carcinoma.

The observations presented here indicate a metastasis suppressor role for TGFβ signaling in human colon cancer cells. This raises the concern that therapies targeting inhibition of TGFβ signaling may be imprudent in some patient populations with residual TGFβ tumor suppressor activity.

• biomarker
• epidermal growth factor receptor
• monoclonal antibody
• resistance
• tyrosine kinase inhibitor

• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/enzymology
• Drug Discovery/methods
• Drug Resistance, Neoplasm/drug effects
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/immunology
• ErbB Receptors/metabolism
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/enzymology
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use

Understanding drivers for metastasis in human cancer is important for potential development of therapies to treat metastases. The role of loss of TGFβ tumor suppressor activities in the metastatic process is essentially unknown.

Utilizing in vitro and in vivo techniques, we have shown that loss of TGFβ tumor suppressor signaling is necessary to allow the last step of the metastatic process - colonization of the metastatic site. This work demonstrates for the first time that TGFβ receptor reconstitution leads to decreased metastatic colonization. Moreover, we have identified a novel TGFβ/PKA tumor suppressor pathway that acts directly on a known cell survival mechanism that responds to stress with the survivin/XIAP dependent inhibition of caspases that effect apoptosis. The linkage between the TGFβ/PKA transduceome signaling and control of metastasis through induction of cell death was shown by TGFβ receptor restoration with reactivation of the TGFβ/PKA pathway in receptor deficient metastatic colon cancer cells leading to control of aberrant cell survival.

This work impacts our understanding of the possible mechanisms that are critical to the growth and maintenance of metastases as well as understanding of a novel TGFβ function as a metastatic suppressor. These results raise the possibility that regeneration of attenuated TGFβ signaling would be an effective target in the treatment of metastasis. Our work indicates the clinical potential for developing anti-metastasis therapy based on inhibition of this very important aberrant cell survival mechanism by the multifaceted TGFβ/PKA transduceome induced pathway. Development of effective treatments for metastatic disease is a pressing need since metastases are the major cause of death in solid tumors.

• Animals
• Cell Survival
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Models, Biological
• Neoplasm Metastasis
• Neoplasm Transplantation
• Signal Transduction
• Transforming Growth Factor beta/metabolism

• R37 CA038173 NCI NIH HHS
• R01 CA038173 NCI NIH HHS
• CA38173 NCI NIH HHS
• CA72001 NCI NIH HHS
• R01 CA072001 NCI NIH HHS

• adnectin
• biologics
• egfr
• igf-ir
• bispecific

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal/metabolism
• Antibodies, Monoclonal/pharmacology
• Antibodies, Monoclonal, Humanized
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Dose-Response Relationship, Drug
• ErbB Receptors/antagonists & inhibitors
• ErbB Receptors/metabolism
• Female
• Fibronectins/chemistry
• Humans
• Immunoblotting
• Kinetics
• Mice
• Mice, Nude
• Molecular Sequence Data
• Panitumumab
• Peptide Fragments/metabolism
• Peptide Fragments/pharmacology
• Phosphorylation/drug effects
• Protein Binding
• Receptor, IGF Type 1/antagonists & inhibitors
• Receptor, IGF Type 1/metabolism
• Signal Transduction/drug effects
• Tumor Burden/drug effects
• Xenograft Model Antitumor Assays