A JAK2/STAT5-mediated positive feedback loop promotes resistance to PI3K/mTOR inhibition.

  • Major finding: A JAK2/STAT5-mediated positive feedback loop promotes resistance to PI3K/mTOR inhibition.

  • Mechanism: IRS1-activated JAK2/STAT5 induces IL-8 to enhance JAK2 signaling and cancer cell invasion.

  • Impact: Dual PI3K/mTOR and JAK2 blockade may reduce TNBC growth and metastasis and increase survival.

Inhibitors of phosphoinositide 3-kinase (PI3K)/mTOR signaling, which is hyperactivated in many tumors, including triple-negative breast cancer (TNBC), are being tested as potential targeted therapeutics. However, reactivation of AKT and other survival signals in resistant tumors limits the efficacy of these inhibitors, emphasizing the need for combinatorial therapies. Britschgi and colleagues sought to elucidate the mechanisms underlying resistance in TNBC and found that phosphorylation of Janus-kinase 2 (JAK2) and its effector STAT5 was increased by treatment with the PI3K/mTOR inhibitor BEZ235. Upregulation of insulin receptor substrate 1 (IRS1) in response to BEZ235 was required for initial activation of JAK2/STAT5, which induced expression of interleukin (IL)-8, a prometastatic cytokine. Secreted IL-8 further augmented JAK2/STAT5 activation in TNBC cells via interaction with chemokine (C-X-C motif) receptor 1 (CXCR1) in a positive feedback loop. Increased JAK2/STAT5 phosphorylation and elevated expression of IL-8 were also detected in primary human breast tumors and were correlated with BEZ235 insensitivity and enhanced metastatic potential in TNBC cell lines, suggesting that JAK2 signaling contributes to resistance to PI3K/mTOR inhibitors and tumor progression. Consistent with this idea, combined inhibition of PI3K/mTOR and JAK2 resulted in sustained AKT suppression, reduced cancer cell viability, and increased apoptosis compared with single-agent treatment. Moreover, PI3K/mTOR and JAK2 inhibitors synergistically diminished tumor growth, decreased circulating tumor cells, and impaired lung metastasis, and treatment with this combination prolonged both the event-free and overall survival of tumor-bearing mice. This effect was mediated by the induction of apoptosis in CXCR1-positive tumor-initiating cells upon inhibition of JAK2 or dual inhibition of PI3K/mTOR and JAK2. These results identify JAK2-driven IL-8/CXCR1 signaling as a critical resistance mechanism in TNBC and suggest that simultaneous targeting of JAK2 may improve the efficacy of PI3K/mTOR inhibitors in patients with metastatic breast cancer.

Britschgi A, Andraos R, Brinkhaus H, Klebba I, Romanet V, Müller U, et al. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell 2012;22:796–811.