Effect of FAK inhibitor VS‐6063 (defactinib) on docetaxel efficacy in prostate cancer

Lin, Hui-Ming; Lee, Brian Y.; Castillo, Lesley; Spielman, Calan; Grogan, Judith; Yeung, Nicole; Kench, James G.; Stricker, Phillip D.; Haynes, Anne Maree; Centenera, Margaret M.; Butler, Lisa M.; Shreeve, S. Martin; Horvath, Lisa G.; Daly, Roger J.

doi:10.1002/pros.23476

Cited by 51 publications

(37 citation statements)

References 25 publications

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“…Increased phosphorylation of FAK at Y925 was observed within our prostate CAF compared with patient-matched NPF, indicating that this may represent a common microenvironmental signaling pathway across different solid tumor types (51, 54). Further, a recent study has shown that FAK is up-regulated during prostate cancer progression and promotes resistance to chemotherapy (82), supporting the use of concomitant FAK inhibitors with standard-of-care treatment. Similarly, next generation LOXL2 inhibitors are effective in pre-clinical models of gastric (83) and breast cancer (40, 84, 85) as well as lung and liver fibrosis models (86), with targeted therapeutics against LOXL2 currently undergoing Phase I/II testing (54).…”

Section: Discussionmentioning

confidence: 98%

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment

Nguyen

Pereira

Lawrence

et al. 2019

Molecular & Cellular Proteomics

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Mass spectrometry-based (phospho)proteomics identified a prominent hub associated with collagens, receptor tyrosine kinase discoidin domain-containing receptor 2 (DDR2), and lysyl oxidase-like 2 (LOXL2) from patient-matched cancer-associated fibroblasts (CAF) and non-malignant prostate fibroblasts (NPF). The functional role of LOXL2 in regulating ECM organization and migration of both CAF and co-cultured prostate cancer cells was validated with LOXL2 inhibitors. Our data provide the first demonstration that prostate CAF-dependent LOXL2 production controls prostate tumor cell motility, highlighting LOXL2 as an attractive therapeutic target.

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Section: Discussionmentioning

confidence: 98%

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment

Nguyen

Pereira

Lawrence

et al. 2019

Molecular & Cellular Proteomics

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“…For example, the CD47 blocking protein TTI-621 (Petrova et al, 2017) is currently being assessed in a number of phase I clinical trials (NCT03013218, NCT02663518, NCT02216409, NCT02678338) for various types of cancers. Other groups have targeted FAK with the inhibitor VS-6063 (Defactinib) (Lin et al, 2018), which has completed clinical phase I and II trials (NCT01778803, NCT01943292, NCT01951690) with one of those clinical trials assessing for CSCs as an endpoint (NCT01778803). Other inhibitors of stemness-related molecules further downstream of ECM signaling are also being tested in clinical trials, such as the STAT3 inhibitor BBI-608 (Sonbol et al, 2019) in a phase II trial that will test for presence of CSC as an endpoint (NCT02279719) and in a phase III clinical trial aimed at reducing CSCs by targeting phosphorylated Stat3 positive cancer cells (NCT02753127).…”

Section: Csc Targeting Therapiesmentioning

confidence: 99%

The Role of the Extracellular Matrix in Cancer Stemness

Nallanthighal

Heiserman

Cheon

2019

Front. Cell Dev. Biol.

257

200

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As our understanding of cancer cell biology progresses, it has become clear that tumors are a heterogenous mixture of different cell populations, some of which contain so called “cancer stem cells” (CSCs). Hallmarks of CSCs include self-renewing capability, tumor-initiating capacity and chemoresistance. The extracellular matrix (ECM), a major structural component of the tumor microenvironment, is a highly dynamic structure and increasing evidence suggests that ECM proteins establish a physical and biochemical niche for CSCs. In cancer, abnormal ECM dynamics occur due to disrupted balance between ECM synthesis and secretion and altered expression of matrix-remodeling enzymes. Tumor-derived ECM is biochemically distinct in its composition and is stiffer compared to normal ECM. In this review, we will provide a brief overview of how different components of the ECM modulate CSC properties then discuss how physical, mechanical, and biochemical cues from the ECM drive cancer stemness. Given the fact that current CSC targeting therapies face many challenges, a better understanding of CSC-ECM interactions will be crucial to identify more effective therapeutic strategies to eliminate CSCs.

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“…So, the drug combination therapy can show better results in cancer treatment especially in PCa because most of the PCa patients become androgen resistant upon androgen ablation therapy . Moreover, docetaxel is the most common chemotherapeutic agent used in PCa where a combination treatment of focal adhesion kinase (FAK) inhibitor VS‐6063 with docetaxel found higher growth inhibition and increased apoptosis in PCa cell line PC3 . In another study on PCa, the combination treatment of docetaxel and curcumin repressed the cell proliferation and prompted apoptosis significantly higher than the single treatment of either docetaxel or curcumin by repressing the expression of EGFR, HER2, RTKs, PI3K, pAkt, NF‐kappa B, and COX‐2 and by increasing the expression of proapoptotic proteins P53, BAX, BAKm and BID .…”

Section: Targeting Oncogenic Deubiquitinase As the Possible Therapeuticsmentioning

confidence: 99%

Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

Islam

Zhou

Chen

et al. 2019

Cell Biochemistry & Function

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Prostate cancer (PCa) is the most common cancer diagnosed and the second most common cause of cancer‐related death in men worldwide. The current androgen deprivation therapy for PCa cannot fully cure this disease. Moreover, androgen receptor gene amplification and mutation are associated with PCa to develop castration‐resistant prostate cancer (CRPC). This review focuses on the deubiquitinases (DUBs) involved in PCa development and progression. For PCa development and progression, several cellular pathways are regulated by specific DUBs which are also highlighted in here. The ubiquitin‐specific proteases (USPs), a family member of DUBs mostly involved in the regulation of cellular pathways for PCa development, and the ubiquitin C‐terminal hydrolases (UCHs), another family member of DUBs, are responsible for PCa metastasis. Small molecular inhibitors against DUBs can inhibit or reduce the level of specific DUBs through the regulation of cellular pathway to treat this disease. Some small molecular inhibitors are already identified against some of the DUBs, but very few of them are clinically proved in PCa. So, to find out other DUBs involving in the regulation of PCa‐related pathways and to develop more effective small molecule inhibitors with greater potency would be a great idea to target PCa cells for future therapeutics and drug development with or without the combination of other anticancer drugs. Significance of the study This review is targeting DUB proteins which are responsible for PCa induction, proliferation, and metastasis by highlighting their signalling pathway so that the readers can get information about other mechanisms for PCa besides androgen receptor pathway and helps to find other oncogenic DUBs involving in these signalling pathways. This review also hopes to find other oncogenic DUBs involving in PCa‐related signalling pathways or to find the DUBs that can regulate multiple oncogenic signalling pathways which might be a good target for PCa therapeutics. In addition, there are some small molecule inhibitors that can inhibit the oncogenic DUBs and thus able to control the oncogenic pathways which would be a novel strategy to treat CRPC by using DUB inhibitor combined with or without other anticancer drugs.

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Effect of FAK inhibitor VS‐6063 (defactinib) on docetaxel efficacy in prostate cancer

Abstract: Our findings suggest that co-administration of the FAK inhibitor, VS-6063, with docetaxel represents a potential therapeutic strategy to overcome docetaxel resistance in prostate cancer.

Cited by 51 publications

References 25 publications

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment

Proteomic Profiling of Human Prostate Cancer-associated Fibroblasts (CAF) Reveals LOXL2-dependent Regulation of the Tumor Microenvironment

The Role of the Extracellular Matrix in Cancer Stemness

Targeting the signalling pathways regulated by deubiquitinases for prostate cancer therapeutics

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