Novel, Targetable Mechanism of Resistance Identified in Breast Cancer

Scientists have identified a novel way metastatic breast cancer cells can bypass targeted therapy. Breast cancer cells with an active phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway treated with a PI3K inhibitor are able to turn up a different pathway, the Janus family of kinases and associated signal transducers and activators of transcription (JAK2/STAT5) pathway, and continue to grow. The results, published in Cancer Cell have broad implications because the PI3K pathway is important in a variety of different cancers.

Key elements of the JAK-STAT pathway

Mohamed Bentires-Alj, PhD, of the Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland, and colleagues, including those at the Novartis Institutes for Biomedical Research, Basel, used both in vitro and mouse tumor models of triple-negative breast cancer to identify the resistance pathways of cells treated with a PI3K/mTOR inhibitor. The researchers found that inhibition of the PI3K pathway results in activation of JAK2/STAT5, which then stimulates secretion of IL-8, a cytokine that promotes metastasis. This cytokine can then stimulate JAK2/STAT5 further, creating a feedback loop.

The JAK/STAT pathway also functions broadly in cell growth, differentiation, survival, as well as migration.

The results suggest the need to assess whether JAK2/STAT5 is already active before treating a cancer with a PI3K/mTOR inhibitor. The important finding, said Bentires-Alj, “is that the efficacy of PI3K/mTOR inhibition can be improved dramatically by simultaneous JAK2 inhibition.” This combination is able to reduce the number of circulating tumor cells, the spread of metastasis, and therefore increase survival of the metastatic mouse tumor model used in the studies.

The study highlights the critical importance of understanding the pathways that can drive tumor growth. A road map of the circuitry of the cancer cell is necessary so that when faced with a roadblock in the form of a targeted agent, clinicians can anticipate alternative routes that the cancer cell can use. Blocking all of the potential growth pathways is the ultimate goal of targeted therapy. Based on accumulating findings in both patients and the laboratory, combination therapy is the realistic way to improve survival for patients.

“Cancers often develop resistance to therapies, including the novel molecularly targeted therapies, and especially when used as a single agent,” said Bentires-Alj. “We need to gain a better understanding of the wiring diagram of cancer cells in order to anticipate resistance mechanisms and plan the right combination therapies.” Bentires-Alj also believes that there needs to be a better understanding of how cancers progress to metastasis.

The study used the PI3K/mTOR inhibitor, BEZ235, currently in phase II trials for renal cell carcinoma and beast cancer, among other cancers. The drug is being developed by Novartis both as a monotherapy and in combination with chemotherapy and targeted agents. JAK2 inhibition was achieved with NVP-BSK805, a novel JAK2 inhibitor also developed by Novartis that has not yet been tested in human clinical trials.

Mice with aggressive triple-negative–type tumors treated with both a PI3K/mTOR and JAK2 inhibitor had slower growing tumors that were less likely to metastasize, resulting in longer survival of the mice.

These results support the combination of JAK2 and PI3K/mTOR inhibitors in the clinic. The data also “suggest IL-8 as a predictor of the efficacy of PI3K/mTOR inhibition,” state the authors.

Imatinib for Philadelphia chromosome–positive chronic myeloid leukemia (CML) and BRAF inhibitors for metastatic melanoma patients that harbor an activating V600E BRAF mutation are examples of successful agents that target a necessary driver of tumor growth. Treatment of CML and melanoma with these agents results in rapid tumor shrinkage and improvement in overall survival. However, few targeted agents have been able to achieve long-term overall survival for cancer patients because the tumor cells are able to genetically adapt, bypassing the need for a driver mutation with activation of another. As the authors of this paper demonstrate and highlight in this study, understanding the “wiring diagram” of cancer cells and anticipating mechanisms of resistance to targeted agents is crucial for successful targeted therapy.

“This strategy needs to be first evaluated in clinical trials,” said Bentires-Alj. “We hope that our findings will be tested in clinical trials and that the right patients will be selected for these studies.” Bentires-Alj noted that discussions to plan clinical trials are in the progress.

The study focused on PI3K inhibition partly because this pathway is one of the most highly activated pathways in cancer as it has functions in cell growth, survival, metabolism, and even motility. According to the authors, 26 compounds that target the PI3K/mTOR pathway are currently in clinical trials.

“This work is an excellent example of a collaboration between an academic institution pursuing basic research and industry, and illustrates how we can work together to address an unmet medical need for the benefit of patients,” said Bentires-Alj.