Hyperactivated mTOR and JAK2/STAT3 Pathways: Molecular Drivers and Potential Therapeutic Targets of Inflammatory and Invasive Ductal Breast Cancers After Neoadjuvant Chemotherapy

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• 作者：Komal Jhaveri¹ ; ^{jhaverik@mskcc.org" class="auth_mail" title="E-mail the corresponding author} ; Eleonora Teplinsky² ; Deborah Silvera³ ; Amanda Valeta-Magara³ ; Rezina Arju³ ; Shah Giashuddin⁴ ; Yasmeen Sarfraz³ ; Melissa Alexander⁴ ; Farbod Darvishian⁴ ; Paul H. Levine⁵ ; Salman Hashmi⁶ ; Ladan Zolfaghari⁶ ; Heather J. Hoffman⁶ ; Baljit Singh⁵ ; Judith D. Goldberg⁶ ; Tsivia Hochman⁶ ; Silvia Formenti⁷ ; Francisco J. Esteva¹ ; Meena S. Moran⁸ ; Robert J. Schneider¹ ; ³
• 关键词：Biomarkers ; Inflammatory breast cancer ; Resistance to chemotherapy ; Signaling pathways ; Targeted therapies
• 刊名：Clinical Breast Cancer
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：16
• 期：2
• 页码：113-122.e1
• 全文大小：779 K

文摘

Inflammatory breast cancer (IBC) is an aggressive and rare cancer with a poor prognosis and a need for novel targeted therapeutic strategies. Preclinical IBC data showed strong activation of the phosphatidylinositide-3-kinase/mammalian target of rapamycin (mTOR) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, and expression of inflammatory cytokines and tumor-associated macrophages (TAMs).

Patients and Methods

Archival tumor tissue from 3 disease types (IBC treated with neoadjuvant chemotherapy [NAC], n = 45; invasive ductal carcinoma [IDC] treated with NAC [n = 24; ‘treated IDC’; and untreated IDC [n = 27; ‘untreated IDC’]) was analyzed for the expression of biomarkers phospho-S6 (pS6) (mTOR), phospho-JAK2 (pJAK2), pSTAT3, interleukin (IL)-6, CD68 (monocytes, macrophages), and CD163 (TAMs). Surrounding nontumor tissue was also analyzed.

Results

Biomarker levels and surrogate activity according to site-specific phosphorylation were shown in the tumor tissue of all 3 disease types but were greatest in IBC and treated IDC and least in untreated IDC for pS6, pJAK2, pSTAT3, and IL-6. Of 37 IBC patients with complete biomarker data available, 100% were pS6-positive and 95% were pJAK2-positive. In nontumor tissue, biomarker levels were observed in all groups but were generally greatest in untreated IDC and least in IBC, except for JAK2.

Conclusion

IBC and treated IDC display similar levels of mTOR and JAK2 biomarker activation, which suggests a potential mechanism of resistance after NAC. Biomarker levels in surrounding nontumor tissue suggested that the stroma might be activated by chemotherapy and resembles the oncogenic tumor-promoting environment. Activation of pS6 and pJAK2 in IBC might support dual targeting of the mTOR and JAK/STAT pathways, and the need for prospective studies to investigate combined targeted therapies in IBC.