JAK2-STAT5 signaling: A novel mechanism of resistance to targeted PI3K/mTOR inhibition.
A recent article published by Britschgi et al. in Cancer Cell, "JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer," describes a positive feedback loop of JAK2/STAT5 activation that drives resistance to PI3K/mTOR inhibition in breast cancer. The authors found that genetic or pharmacological inhibition of JAK2 circumvents resistance to PI3K/mTOR inhibition and go on to show the efficacy of combined PI3K/mTOR and JAK2 inhibition on reducing cancer cell number, tumor growth, and metastasis as well as increasing in vivo survival. These results provide strong support for combination therapy with JAK2/STAT5 and PI3K/mTOR inhibitors in breast cancer. Here we discuss how the article by Britschgi et al. proposes a novel mechanism to explain how breast cancer cells overcome inhibition of a key signaling pathway driving cell proliferation. We also discuss the interplay between activation of the transcription factors STAT5 and STAT3 in breast cancer.
Department of Medical Oncology; Dana-Farber Cancer Institute; and Departments of Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA.
Jennifer E
JE
Yeh
Department of Medical Oncology; Dana-Farber Cancer Institute; and Departments of Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA ; Institute of Biomedical Science; Department of Immunology; University of Sao Paulo; Sao Paulo, Brazil.
Patricia A
PA
Toniolo
Department of Medical Oncology; Dana-Farber Cancer Institute; and Departments of Medicine; Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA.
David A
DA
Frank
breast cancer; kinases; signal transduction; targeted therapy; transcription factors