Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors

Sommer, Eeva; Dry, Hannah; Cross, Darren A.E.; Guichard, Sylvie; Davies, Barry R.; Alessi, Dario R.

doi:10.1042/bj20130342

Cited by 143 publications

(167 citation statements)

References 39 publications

Supporting

Mentioning

158

Contrasting

Order By: Relevance

“…Interestingly, two of these lines, MDA-MB-157 and MDA-MB-436, were not responsive to AZD5363. SGK-1 expression activation has recently been shown to be associated with reduction in sensitivity to AKT inhibition in breast cancer cell lines (18). Although a relationship is seen as expected between SGK-1 expression and sensitivity to AZD5363, the relationship is not as clear for AZD8186 (Fig.…”

Section: Azd8186 Inhibits Akt Pathway Activation and Growth Of Multipmentioning

confidence: 62%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kb isoform. Inhibitors of PI3Kb have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kb and PI3Kd (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI 50 < 1 mmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kb with activity against PI3Kd signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.

show abstract

Section: Azd8186 Inhibits Akt Pathway Activation and Growth Of Multipmentioning

confidence: 62%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, our findings are also consistent with data suggesting that SGK-1 activity can mediate the sensitivity of cancer cells to targeted therapies. 34 It is noteworthy that other investigators have discovered that SGK-1 can interact with proteins at the mitochondria and can inhibit the induction of necrotic cell death. 19,35 Our data implicating SGK-1 in ATP generation may provide additional insight into these connections between SGK-1 and mitochondrial integrity.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

et al. 2016

View full text Add to dashboard Cite

In order for cancer cells to survive during metastasis, they must overcome anoikis, a caspase-dependent cell death process triggered by extracellular matrix (ECM) detachment, and rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals used by cancer cells to facilitate their survival during metastasis remain poorly understood. We have discovered that oncogenic Ras facilitates the survival of ECM-detached cancer cells by using distinct effector pathways to regulate metabolism and block anoikis. Surprisingly, we find that while Ras-mediated phosphatidylinositol (3)-kinase signaling is critical for rectifying ECM-detachment-induced metabolic deficiencies, the critical downstream effector is serum and glucocorticoid-regulated kinase-1 (SGK-1) rather than Akt. Our data also indicate that oncogenic Ras blocks anoikis by diminishing expression of the phosphatase PHLPP1 (PH Domain and Leucine-Rich Repeat Protein Phosphatase 1), which promotes anoikis through the activation of p38 MAPK. Thus, our study represents a novel paradigm whereby oncogene-initiated signal transduction can promote the survival of ECM-detached cells through divergent downstream effectors. Cell Death and Differentiation (2016) 23, 1271-1282 doi:10.1038/cdd.2016 published online 26 February 2016 Cancer metastasis, the spread of cancer cells to distant parts of the body, accounts for~90% of cancer-related deaths and represents an inherently difficult clinical challenge.1,2 It has become clear that for successful metastasis to occur, cells must overcome a caspase-dependent cell death mechanism, anoikis, which is triggered by detachment from the extracellular matrix (ECM).3 In addition to anoikis evasion, cancer cells must also contend with anoikis-independent cellular alterations that can compromise cellular viability. 4 Chief among these alterations are metabolic deficiencies that are induced by ECM detachment. [5][6][7] These metabolic alterations involve deficiencies in ATP generation, elevated levels of reactive oxygen species, and the induction of autophagy. 6,8,9 Although recent studies have begun to unravel the strategies used by cancer cells to ameliorate metabolic deficiencies during ECM detachment, 10 the signal-transduction cascades responsible for regulating metabolism during ECM detachment in cancer cells remain almost entirely unexplored.The activation of oncogenic signaling pathways is critical to anchorage-independent growth and ultimately to the survival of a variety of distinct cancer cell types during ECM detachment. 4,11 Presumably, this oncogenic signaling is also necessary for resolving the aforementioned ECM-detachment-induced metabolic deficiencies. ErbB2 overexpression in mammary epithelial cells results in a stimulation of phosphatidylinositol (3)-kinase (PI(3)K)/Akt signaling to promote glucose uptake and ATP generation.6 These data raise the question as to how cancer cells that lack ErbB2 overexpression rectify metabolic deficiencies during ECM detachment. Does activation o...

show abstract

“…Response of pNDRG1 to AKT inhibition in breast cancer cell lines is variable. Some cell lines respond to AKT inhibition with a decrease in NDRG1 phosphorylation, whereas others do not (18). We found that NDRG1 phosphorylation was suppressed in cells treated with inhibitors of PI3K (BKM120, BYL719, PIK75, and TGX221) and AKT (MK2206 and GSK650394) but not inhibitors of PARP (Olaparib) or MAPK (GSK112021), i.e., we found that NDRG1 phosphorylation in HCC1937 cells was responsive to PI3K and AKT inhibition, confirming these previous reports of cross-talk between PI3K, AKT, and mTOR signaling (but excluding ERK signaling) with regard to SGK activity.…”

Section: Pi3kmentioning

confidence: 99%

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Juvekar

Yadegarynia

et al. 2016

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

View full text Add to dashboard Cite

We previously reported that combining a phosphoinositide 3-kinase (PI3K) inhibitor with a poly-ADP Rib polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. Here, we show that enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of nucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four nucleotide triphosphates, whereas inhibition of the protein kinase AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage. Carbon flux studies reveal that PI3K inhibition disproportionately affects the nonoxidative pentose phosphate pathway that delivers Rib-5-phosphate required for base ribosylation. In vivo in a mouse model of BRCA1-linked triple-negative breast cancer (K14-Cre BRCA1), the PI3K inhibitor BKM120 led to a precipitous drop in DNA synthesis within 8 h of drug treatment, whereas DNA synthesis in normal tissues was less affected. In this mouse model, combined PI3K and PARP inhibition was superior to either agent alone to induce durable remissions of established tumors. T riple-negative breast cancers, including BRCA1-linked breast cancers, frequently show activation of the PI3K pathway as a result of overexpression of epidermal growth factor receptor (EGFR) (1, 2) or insulin-like growth factor 1 receptor (IGFR) (3), and inhibition of the EGFR (1, 2, 4) and/or the PI3K/Nrf2 axis (5) prevents cancers arising from BRCA1 mutant mammary epithelial cells (MECs). In addition, activating mutations of PIK3CA, or loss of the inhibitory lipid phosphatases PTEN (phosphatase and tensin homolog) and INPP4B (inositol polyphosphate 4-phosphatase type II) (6, 7), suggest that the PI3K pathway is contributing to tumor growth and survival. Aside from their role in regulating the homeostasis of phospho-inositides, PTEN and INPP4B may have independent roles in DNA damage repair. A role for PTEN in the maintenance of genomic stability was identified (8); more recently, INPP4B was found to directly interact with BRCA1 and the serine/threonine protein kinase ATR, and its loss destabilizes these DNA damage repair complexes, effectively sensitizing INPP4B-deficient cells to poly-ADP Rib polymerase (PARP) inhibition (9).Despite the high incidence of predisposing lesions in the PI3K pathway, limited clinical activity has been observed with PI3K inhibitors as single-agent treatment in endocrine-resistant breast cancer, which may reflect bypass of PI3K-dependent mitogenic signaling by alternative signaling pathways such as the MAPK pathway. Therefore, concurrent inhibition of parallel and compensatory signaling networks to overcome resistance to PI3K inhibition is being investigated in clinical studies. This approach, however, carries the risk of overlapping toxicities of the targeted agents without sufficient efficacy because tumor cells may have greater plasticity for redundant signaling than normal tissues.Mul...

show abstract

Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors

Cited by 143 publications

References 39 publications

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Contact Info

Product

Resources

About