Inhibition of the p38 Kinase Suppresses the Proliferation of Human ER-Negative Breast Cancer Cells

Chen, Lü; Mayer, Julie Ann; Krisko, Tibor I.; Speers, Corey; Wang, Tao; Hilsenbeck, Susan G.; Brown, Powel H.

doi:10.1158/0008-5472.can-09-1636

Cited by 117 publications

(95 citation statements)

References 48 publications

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“…The role of p38a in breast cancers has been studied in depth and very recently proposed as a therapeutic target in TNBC (56,57). ER-negative and mutant-p53 cell lines (which comprise the majority of TNBCs) were observed to be more sensitive to small-molecule inhibition of p38a than ER-positive and wt-p53 cell lines (58). The exact contribution of p38b to MAPK signaling has not been fully elucidated; however, there is growing evidence that p38b activity correlates with increased proliferation of TNBC cells (57,59,60).…”

Section: Discussionmentioning

confidence: 99%

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Gilani

Phadke

Bao

et al. 2016

Clinical Cancer Research

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Purpose: c-Src has been shown to play a pivotal role in breast cancer progression, metastasis, and angiogenesis. In the clinic, however, the limited efficacy and high toxicity of existing c-Src inhibitors have tempered the enthusiasm for targeting c-Src. We developed a novel c-Src inhibitor (UM-164) that specifically binds the DFG-out inactive conformation of its target kinases. We hypothesized that binding the inactive kinase conformation would lead to improved pharmacologic outcomes by altering the noncatalytic functions of the targeted kinases.Experimental Design: We have analyzed the anti-triple-negative breast cancer (TNBC) activity of UM-164 in a comprehensive manner that includes in vitro cell proliferation, migration, and invasion assays (including a novel patient-derived xenograft cell line, VARI-068), along with in vivo TNBC xenografts. Results:We demonstrate that UM-164 binds the inactive kinase conformation of c-Src. Kinome-wide profiling of UM-164 identified that Src and p38 kinase families were potently inhibited by UM-164. We further demonstrate that dual c-Src/p38 inhibition is superior to mono-inhibition of c-Src or p38 alone. We demonstrate that UM-164 alters the cell localization of c-Src in TNBC cells. In xenograft models of TNBC, UM-164 resulted in a significant decrease of tumor growth compared with controls, with limited in vivo toxicity.Conclusions: In contrast with c-Src kinase inhibitors used in the clinic (1, 2), we demonstrate in vivo efficacy in xenograft models of TNBC. Our results suggest that the dual activity drug UM-164 is a promising lead compound for developing the first targeted therapeutic strategy against TNBC.

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Section: Discussionmentioning

confidence: 99%

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

Gilani

Phadke

Bao

et al. 2016

Clinical Cancer Research

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“…Transfection and validation were conducted as described previously (12). Growth assays were conducted in triplicate and repeated independently as described previously using Trypan blue to identify live, viable cells and manual quantification with hemocytometers (27).…”

Section: Methodsmentioning

confidence: 99%

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Haricharan

Brown

2015

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-γ) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types.reast cancer has one of the highest incidence rates of cancer in women worldwide, with more than 1.5 million women diagnosed with the disease in 2012. Owing to its high incidence, breast cancer is also one of the leading causes of cancer-related deaths, with 40,000 women predicted to die of the disease in 2014 in the US alone. The diagnosis and treatment of breast cancer has been significantly improved by the identification of three major subtypes of the disease based on receptor expression: estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple-negative [tumors lacking ER, progesterone receptor (PR), and HER2]. Of these subtypes, ER-positive breast cancer accounts for 70-80% of all diagnosed breast tumors.ER-positive breast cancer is largely responsive to endocrine therapy; however, intrinsic or acquired resistance occurs in onethird of cases and contributes significantly to breast cancerassociated mortality. Therefore, identifying therapeutic targets to prevent ER-positive breast cancer mortality is a major focus of scientific investigation. ER-positive breast tumors with a high mutation load are associated with poor patient survival, and a high mutation load likely affects the response to endocrine therapy (1). Because known drivers of endocrine resistance (e.g., PR negativity and HER2 amplification) are not enriched in this subset, the identification of no...

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“…P38 MAPK is comprised of four isoforms (α, β, γ and δ) that can be activated by various growth factors, inflammatory cytokines, and chemical or physical stress. The α isoform is the most abundant and is subject to a larger inter-individual variability than the other three isoforms (12). P38 MAPK plays a complex role in the regulation of cell growth, differentiation, apoptosis, and responses to inflammation or stress (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…The role of P38 MAPK in the regulation of breast cancer cell proliferation remains to be elucidated and has been suggested to have dual activities that include regulation of survival and proliferation depending on the expression of mutant TP53 (12) as observed in most ER -breast tumors therefore justifying the development of P38 MAPK inhibitors for the treatment of TP53-mutated, ER -breast cancers or TNBCs. Furthermore, the activation of P38 MAPK has recently been reported to regulate signaling by EGFR/c-Src crosstalk in breast cancer (13).…”

Section: Introductionmentioning

confidence: 99%

Expression and activation of P38 MAP kinase in invasive ductal breast cancers: Correlation with expression of the estrogen receptor, HER2 and downstream signaling phosphorylated proteins

Merlin¹,

Harlé²,

Lion³

et al. 2013

Oncology Reports

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Abstract. MAP kinase signaling proteins have major implications in the molecular oncogenesis of breast cancers and have been extensively investigated as putative targets for therapy. This study reports the investigation of the expression of P38 MAPK and its phosphorylated form (p-P38 MAPK) in clinical specimens of invasive breast carcinomas and their correlation with estrogen receptor (ER) and HER2 expression, as well as MAPK and PI3 kinase-AKT pathway signaling phosphorylated proteins. Expression levels of P38 MAPK and p-P38 MAPK as well as p-AKT, p-GSK3β, p-S6 kinase, p-MEK1 and p-ERK1/2 were quantitatively assessed using multiplex bead immunoassay in frozen specimens from 45 invasive ductal breast cancers. Twenty-nine specimens were ER + , 15 were HER2 + and 10 were triple-negative breast cancers (TNBCs). P38 MAPK was found to be expressed in all tumor specimens and was significantly (P= 0.002) overexpressed in ER + tumors. P38 MAPK expression was lower in TNBCs than in all of the other tumors.

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Inhibition of the p38 Kinase Suppresses the Proliferation of Human ER-Negative Breast Cancer Cells

Cited by 117 publications

References 48 publications

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

UM-164: A Potent c-Src/p38 Kinase Inhibitor with In Vivo Activity against Triple-Negative Breast Cancer

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

Expression and activation of P38 MAP kinase in invasive ductal breast cancers: Correlation with expression of the estrogen receptor, HER2 and downstream signaling phosphorylated proteins

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