JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer

Britschgi, Adrian; Andraos, Rita; Brinkhaus, Heike; Klebba, Ina; Romanet, Vincent; Müller, Urs; Murakami, Masato; Radimerski, Thomas; Bentires‐Alj, Mohamed

doi:10.1016/j.ccr.2012.10.023

Cited by 217 publications

(190 citation statements)

References 58 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…It is also noteworthy that STAT3 activation is observed in stem cell-like cancer cells from different molecular subtypes of breast cancer and targeting JAK2 is effective to treat the triple-negative subtype in preclinical models. [48][49][50] Together, these results suggest a pivotal role for JAK2 irrespective of the receptors mediating activation and thus underscore a generalizable potential for JAK2-targeted therapy to treat multiple forms of this disease.…”

Section: Discussionmentioning

confidence: 94%

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

et al. 2013

View full text Add to dashboard Cite

We previously reported that STAT1 expression is frequently abrogated in human estrogen receptor-a-positive (ERa þ ) breast cancers and mice lacking STAT1 spontaneously develop ERa þ mammary tumors. However, the precise mechanism by which STAT1 suppresses mammary gland tumorigenesis has not been fully elucidated. Here we show that STAT1-deficient mammary epithelial cells (MECs) display persistent prolactin receptor (PrlR) signaling, resulting in activation of JAK2, STAT3 and STAT5A/ 5B, expansion of CD61 þ luminal progenitor cells and development of ERa þ mammary tumors. A failure to upregulate SOCS1, a STAT1-induced inhibitor of JAK2, leads to unopposed oncogenic PrlR signaling in STAT1 À / À MECs. Prophylactic use of a pharmacological JAK2 inhibitor restrains the proportion of luminal progenitors and prevents disease induction. Systemic inhibition of activated JAK2 induces tumor cell death and produces therapeutic regression of pre-existing endocrine-sensitive and refractory mammary tumors. Thus, STAT1 suppresses tumor formation in mammary glands by preventing the natural developmental function of a growth factor signaling pathway from becoming pro-oncogenic. In addition, targeted inhibition of JAK2 may have significant therapeutic potential in controlling ERa þ breast cancer in humans. Cell Death and Differentiation (2014) 21, 234-246; doi:10.1038/cdd.2013.116; published online 13 September 2013Estrogen receptor-a-positive (ERa þ ) breast cancer, the most commonly diagnosed subtype of breast malignancy in women, is routinely treated with combinations of endocrine therapies and radiation or chemotherapy. Nevertheless, half of the patients do not benefit from these treatments because of intrinsic or acquired resistance. 1 Therefore, alternative therapeutic targets in ERa þ breast cancer need to be developed.Work by others has revealed a mammary tumor-promoting effect of prolactin receptor (PrlR) signaling in humans and mice. A meta-analysis of epidemiological data concluded that women in the top quartile for serum prolactin (Prl) concentration have a 60% increased risk of developing ERa þ , but not ERa À , breast cancer, compared with those in the bottom quartile. 2 Consistent with these findings, upregulated PrlR expression and constitutive activation of STAT3 and STAT5 is frequently found in human ERa þ breast cancers. [3][4][5][6]

show abstract

Section: Discussionmentioning

confidence: 94%

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…43 In addition, breast cancer cells reportedly can escape from the therapeutic inhibition of the phosphoinositide-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling cascade by upregulating CXCL8 and hence activating alternative growth-stimulatory pathways. 44 Of note, high expression levels of CXCL8 or CXCR2 have been associated with worsened disease outcome in several types of cancer, including astrocytomas and lung adenocarcinoma. 45,46 Thus, it may appear paradoxical that the CXCL8/CXCR1-2 system is often constitutively active in cancer cells, mainly mediating pro-tumorigenic effects, yet can be hyperactivated by immunogenic chemotherapy to promote CRT exposure and ICD.…”

Section: Discussionmentioning

confidence: 99%

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

Sukkurwala¹,

Martins²,

Wang³

et al. 2013

Cell Death Differ

View full text Add to dashboard Cite

The exposure of calreticulin (CRT) on the surface of stressed and dying cancer cells facilitates their uptake by dendritic cells and the subsequent presentation of tumor-associated antigens to T lymphocytes, hence stimulating an anticancer immune response. The chemotherapeutic agent mitoxantrone (MTX) can stimulate the peripheral relocation of CRT in both human and yeast cells, suggesting that the CRT exposure pathway is phylogenetically conserved. Here, we show that pheromones can act as physiological inducers of CRT exposure in yeast cells, thereby facilitating the formation of mating conjugates, and that a largespectrum inhibitor of G protein-coupled receptors (which resemble the yeast pheromone receptor) prevents CRT exposure in human cancer cells exposed to MTX. An RNA interference screen as well as transcriptome analyses revealed that chemokines, in particular human CXCL8 (best known as interleukin-8) and its mouse ortholog Cxcl2, are involved in the immunogenic translocation of CRT to the outer leaflet of the plasma membrane. MTX stimulated the production of CXCL8 by human cancer cells in vitro and that of Cxcl2 by murine tumors in vivo. The knockdown of CXCL8/Cxcl2 receptors (CXCR1/Cxcr1 and Cxcr2) reduced MTX-induced CRT exposure in both human and murine cancer cells, as well as the capacity of the latter-on exposure to MTX-to elicit an anticancer immune response in vivo. Conversely, the addition of exogenous Cxcl2 increased the immunogenicity of dying cells in a CRT-dependent manner. Altogether, these results identify autocrine and paracrine chemokine signaling circuitries that modulate CRT exposure and the immunogenicity of cell death.

show abstract

“…In our study, we found that a subset of cancer cells exhibited higher levels of JAK2 and S6K1 pathway activation compared with non-malignant cells and were strikingly sensitive to dual inhibition of these two kinases. Although JAK2 inhibitors are indicated for myeloproliferative neoplasms and are being evaluated for other cancers (5,8), certain types of cancers are likely to have limited responses to JAK2 inhibition alone (48,49). S6K1 is a primary downstream effector of mTORC1 signaling, and inhibition of this pathway has been known to cause a cytostatic effect in cancer cells rather than inducing cell death (18,50).…”

Section: Discussionmentioning

confidence: 99%

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

Byun

Lim

Mun

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: An underlying cause of cancer therapeutic resistance is the hyperactivation of endogenous overlapping or redundant signaling pathways in cancer cells. Results: Gingerenone A selectively kills cancer cells through dual inhibition of JAK2 and S6K1. Conclusion: Co-targeting JAK2 and S6K1 induces synergistic anti-cancer effects. Significance: Investigating the targets of bioactive compounds can lead to suggestions for novel therapeutic strategies.

show abstract

JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer

Cited by 217 publications

References 58 publications

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ERα+ tumorigenesis

Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

Contact Info

Product

Resources

About