Kinase-independent role for CRAF-driving tumour radioresistance via CHK2

Advani, Sunil J.; Camargo, M. Fernanda; Seguin, Laetitia; Mielgo, Ainhoa; Anand, Sudarshan; Hicks, Angel M.; Aguilera, Joseph; Franovic, Aleksandra; Weis, Sara M.; Cheresh, David A.

doi:10.1038/ncomms9154

Cited by 42 publications

(42 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, PAK1 modulates the degree of DNA-damage response via directly phosphorylating microrchidia CW-type zinc finger 2 (MORC2-Ser739) and γH2AX (Li et al, 2012). In addition to radiation, PAK1 is stimulated by genotoxic therapeutic agents such as etoposide, and in-turn, PAK1 phosphorylates CRAF-Ser338 and causes radio-resistance (Advani et al, 2015). In general, PAK activation confers survival advantage to cancer cells against DNA-damaging agents, and hence, targeting PAKs has been thought as potential therapeutic approach to sensitize target cells in radiotherapy.…”

Section: Paks In Dna Damage Responsementioning

confidence: 99%

Structure, biochemistry, and biology of PAK kinases

Kumar

Sanawar

et al. 2017

Gene

179

192

View full text Add to dashboard Cite

PAKs, p21-activated kinases, play central roles and act as converging junctions for discrete signals elicited on the cell surface and for a number of intracellular signaling cascades. PAKs phosphorylate a vast number of substrates and act by remodeling cytoskeleton, employing scaffolding, and relocating to distinct subcellular compartments. PAKs affect wide range of processes that are crucial to the cell from regulation of cell motility, survival, redox, metabolism, cell cycle, proliferation, transformation, stress, inflammation, to gene expression. Understandably, their dysregulation disrupts cellular homeostasis and severely impacts key cell functions, and many of those are implicated in a number of human diseases including cancers, neurological disorders, and cardiac disorders. Here we provide an overview of the members of the PAK family and their current status. We give special emphasis to PAK1 and PAK4, the prototypes of groups I and II, for their profound roles in cancer, the nervous system, and the heart. We also highlight other family members. We provide our perspective on the current advancements, their growing importance as strategic therapeutic targets, and our vision on the future of PAKs.

show abstract

Section: Paks In Dna Damage Responsementioning

confidence: 99%

Structure, biochemistry, and biology of PAK kinases

Kumar

Sanawar

et al. 2017

Gene

179

192

View full text Add to dashboard Cite

show abstract

“…Mechanisms of resistance to therapies can be tumor cell intrinsic or mediated by the tumor microenvironment (3). We previously described intrinsic mechanisms of cancer cells' resistance to targeted therapy and radiotherapy (4–6). However, multiple factors can contribute to resistance to therapy and tumor progression, and one dominant player in solid cancers, and specifically in pancreatic cancer, is the presence of a rich protumoral microenvironment (7–10).…”

Section: Introductionmentioning

confidence: 99%

Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors

et al. 2016

Self Cite

View full text Add to dashboard Cite

Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163+ TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention.

show abstract

“…For example, Advani et al . () showed how medication to CRAF_pS338 improves treatment; Duckworth et al . () concluded that overexpression of GAB2 promotes tumor growth; similarly, SF2 has been established as a critical pathway for human cancer cell survival, dissemination, and resistance to drug therapy (Wang et al ., ).…”

Section: Tcpa Protein Expression Datamentioning

confidence: 99%

“…The effects of these proteins on the cancers have been well studied in the literature. For example, Advani et al (2015) showed how medication to CRAF_pS338 improves treatment; Duckworth et al (2016) concluded that overexpression of GAB2 promotes tumor growth; similarly, SF2 has been established as a critical pathway for human cancer cell survival, dissemination, and resistance to drug therapy (Wang et al, 2014). PCADHERIN, FOXO3A_pS318S321, and DIRAS3 are the top 3 proteins recovered by all four chains.…”

Section: Protein Selectionmentioning

confidence: 99%

Bayesian data integration and variable selection for pan‐cancer survival prediction using protein expression data

et al. 2019

View full text Add to dashboard Cite

Accurate prognostic prediction using molecular information is a challenging area of research, which is essential to develop precision medicine. In this paper, we develop translational models to identify major actionable proteins that are associated with clinical outcomes, like the survival time of patients. There are considerable statistical and computational challenges due to the large dimension of the problems. Furthermore, data are available for different tumor types; hence data integration for various tumors is desirable. Having censored survival outcomes escalates one more level of complexity in the inferential procedure. We develop Bayesian hierarchical survival models, which accommodate all the challenges mentioned here. We use the hierarchical Bayesian accelerated failure time model for survival regression. Furthermore, we assume sparse horseshoe prior distribution for the regression coefficients to identify the major proteomic drivers. We borrow strength across tumor groups by introducing a correlation structure among the prior distributions. The proposed methods have been used to analyze data from the recently curated “The Cancer Proteome Atlas” (TCPA), which contains reverse‐phase protein arrays–based high‐quality protein expression data as well as detailed clinical annotation, including survival times. Our simulation and the TCPA data analysis illustrate the efficacy of the proposed integrative model, which links different tumors with the correlated prior structures.

show abstract

Kinase-independent role for CRAF-driving tumour radioresistance via CHK2

Cited by 42 publications

References 39 publications

Structure, biochemistry, and biology of PAK kinases

Structure, biochemistry, and biology of PAK kinases

Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors

Bayesian data integration and variable selection for pan‐cancer survival prediction using protein expression data

Contact Info

Product

Resources

About