JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2-Targeted Therapies.

@article{Manole2016JNKPA,
  title={JNK Pathway Activation Modulates Acquired Resistance to EGFR/HER2-Targeted Therapies.},
  author={S. Manole and Edward J. Richards and Aaron S. Meyer},
  journal={Cancer research},
  year={2016},
  volume={76 18},
  pages={
          5219-28
        }
}
Resistance limits the effectiveness of receptor tyrosine kinase (RTK)-targeted therapies. Combination therapies targeting resistance mechanisms can considerably improve response, but will require an improved understanding of when particular combinations will be effective. One common form of resistance is bypass signaling, wherein RTKs not targeted by an inhibitor can direct reactivation of pathways essential for survival. Although this mechanism of resistance is well appreciated, it is unclear… 
The JNK Pathway in Drug Resistance
IFT20 confers paclitaxel resistance by triggering β-arrestin-1 to modulate ASK1 signaling in breast cancer
TLDR
IFT20 is positively associated with shorter relapse-free survival in patients with system paclitaxel-based chemotherapy and is identified as a promising novel target for overcoming pac litaxel resistance in breast cancer.
A Biomaterial Screening Approach Reveals Microenvironmental Mechanisms of Drug Resistance
TLDR
A novel strategy is provided for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.
JNK Pathway in CNS Pathologies
TLDR
Some newly identified examples and mechanisms of JNK-driven tumor progression in glioblastoma, regeneration/repair after an injury, neurodegeneration and neuronal cell death are discussed.
miR-342-5p as a Potential Regulator of HER2 Breast Cancer Cell Growth.
TLDR
The data suggest that miR-342-5p overexpression in HER2 positive BC cell lines elicits broad effects on HER2 downstream signaling, cell motility and mitochondrial stability, which may render cells less proliferative and more sensitive to cellular stress.
A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance.
TLDR
This work developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response, and found co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone.
89Zr-DFO-Cetuximab as a Molecular Imaging Agent to Identify Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma.
TLDR
It is shown that 89Zr-DFO-cetuximab is suitable for identification of EGFR downregulation in vitro and in vivo and may be useful for monitoring resistance in HNSCC patients during cetUXimab therapy.
Decline in arylsulfatase B expression increases EGFR expression by inhibiting the protein-tyrosine phosphatase SHP2 and activating JNK in prostate cells
TLDR
Findings indicated that ARSB and chondroitin 4-sulfation affect the activation of an important dual phosphorylation threonine–tyrosine kinase and the mRNA expression of a critical tyrosine Kinase receptor in prostate cells.
Zr-DFO-Cetuximab as a Molecular Imaging Agent to Identify Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma
TLDR
The authors showed that Zr-DFO-cetuximab is suitable for identification of EGFR downregulation in vitro and in vivo and may be useful for monitoring resistance in HNSCC patients during cetUXimab therapy.
...
...

References

SHOWING 1-10 OF 29 REFERENCES
COT/MAP3K8 drives resistance to RAF inhibition through MAP kinase pathway reactivation
TLDR
Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
Bypass Mechanisms of Resistance to Receptor Tyrosine Kinase Inhibition in Lung Cancer
TLDR
This mini-review summarizes the concepts underlying RTK-mediated resistance in lung cancer, the specific examples known to date, and the challenges of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
TLDR
It is found that most cells can be rescued from drug sensitivity by simply exposing them to one or more RTK ligands, and the observation that hepatocyte growth factor confers resistance to the BRAF inhibitor PLX4032 in BRAF-mutant melanoma cells is among the findings with clinical implications.
Systematic analysis of BRAFV600E melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis
TLDR
The findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.
The Receptor AXL Diversifies EGFR Signaling and Limits the Response to EGFR-Targeted Inhibitors in Triple-Negative Breast Cancer Cells
TLDR
Machine learning analysis applied to the Cancer Cell Line Encyclopedia database identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)–associated receptor tyrosine kinase (RTK) A XL, as exceptionally predictive of lack of response to ErbB family receptor–targeted inhibitors.
Activation of the AXL Kinase Causes Resistance to EGFR-Targeted Therapy in Lung Cancer
TLDR
Increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation are reported.
Heregulin β1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells
TLDR
HRGβ1 can overcome the inhibitory effects of gefitinib on cell growth and invasion in Tam-R cells through promotion of erbB3/erbB2 heterodimerization and activation of the phosphatidylinositol 3-kinase/AKT signalling pathway.
Antagonism of EGFR and HER3 Enhances the Response to Inhibitors of the PI3K-Akt Pathway in Triple-Negative Breast Cancer
TLDR
Significant evidence is provided that concomitant blockade of EGFR, HER3, and the PI3K-Akt pathway in TNBC should be investigated in the clinical setting and substantially suppressed tumor growth in mice with TNBC xenografts derived from either cell lines or patients.
Signaling pathway models as biomarkers: Patient-specific simulations of JNK activity predict the survival of neuroblastoma patients
TLDR
It is shown that constructing a pathway that reproduces the all-or-nothing, switch-like activation of the stress-activated kinase JNK could be used to stratify neuroblastoma patients, and alterations in the network that prevent the switch- like activation of JNK were associated with poor survival of patients, thus providing potential molecular mechanisms for the inherent resistance of some of these tumors to treatment.
Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC.
...
...