The phosphatidylinositol-3 kinase or PI3K signaling pathway has been identified as a valid target in a large number of cancers. It is probably one of the most important pathways in cancer metabolism and growth. Mutations in the PI3K pathway are frequent in breast cancer, ovarian and endometrial cancers, causing resistance to human epidermal growth factor receptor 2?targeted agents and, possibly, to hormonal agents as well. Available agents that affect the PI3K pathway include monoclonal antibodies and tyrosine kinase inhibitors, as well as PI3K inhibitors, Akt inhibitors, rapamycin analogs, and mammalian target of rapamycin (mTOR) catalytic inhibitors.
Overall, the proportion of breast tumors exhibiting P13K mutations is, depending on the breast cancer subtype, between 20%?25%. In hormone receptor?positive tumors, for example, these mutations occur in >30% of cases. Also, in HER2+ disease, mutations are evident in about one quarter of tumors.[1]
Delaying resistance
Patients with HER2-positive breast cancer being treated with anti-HER2 therapy may be able to prevent or delay resistance to the therapy with the addition of a phosphatidylinositol-3 kinase inhibitor to their treatment regimens.
Trastuzumab (Herceptin?; Genentech/Roche) is approved for treatment of patients with HER2 (ERBB2)-overexpressing breast cancer. A significant fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective.[1][2]
Data published in Cancer Research, a journal of the American Association for Cancer Research, confirms that failure of the anti-HER2 antibody trastuzumab to block HER2 from activating the PI3K signaling pathway can lead to resistance to treatment. Therefore, dual simultaneous inhibition of both HER2 and PI3K may prolong the use of anti-HER2 therapies in women with breast cancer.[2]
?HER2 breast cancer is a subtype of breast cancer for which we have an increasing number of effective treatments, including trastuzumab, an antibody that targets HER2,? said Carlos L. Arteaga, M.D., (photo) director of the Breast Cancer Program at Vanderbilt-Ingram Cancer Center in Nashville, Tenn. ?Unfortunately, many breast cancer tumors learn how to resist this therapy.?
A mechanism of resistance
Arteaga and colleagues explored the possibility that aberrant signaling through the PI3K pathway was a mechanism of resistance to trastuzumab. They used breast cancer models of trastuzumab resistance with different modes of aberrant PI3K pathway activation, and treated the cells with a PI3K inhibitor with or without trastuzumab.
Inhibiting PI3K reduced cancer cells? ability to proliferate and induced the death of trastuzumab-resistant cells. In addition, combining PI3K inhibitors with trastuzumab resulted in superior anti-tumor effects against trastuzumab-resistant, HER2-positive cells in xenografts compared with the PI3K inhibitor alone.
The investigators also conducted analyses to determine how the drug combination decreased resistance to trastuzumab. ?We found that the trastuzumab-resistant cells in which the PI3K pathway was activated had high levels of an anti-death protein called survivin,? Arteaga said. ?This implied that if we could get levels of survivin to decrease, these cells would become sensitive to treatment.?
Higher pretreatment levels
They also measured pretreatment levels of survivin in HER2-positive breast cancer tumors and found that higher pretreatment levels of the protein correlated with a poor response to therapy. ?This suggests that we could measure levels of survivin in tumors, and if they are high or do not decrease with treatment, we could predict that the tumor is resistant to anti-HER2 therapy and try to find alternative treatments,? Arteaga explained.
The researchers plan to continue testing PI3K inhibitors, which are already in early clinical development, in combination with other HER2 drugs in breast cancer. They also plan to measure survivin levels in HER2-overexpressing breast cancer tumors to determine if levels can predict tumors that will benefit from combination treatment.
For more information:
[1] Baselga J. Targeting the Phosphoinositide-3 (PI3) Kinase Pathway in Breast Cancer. The Oncologist 2011 vol. 16 Supplement 1 12-19 doi: 10.1634/theoncologist.2011-S1-12.
[2] Chakrabarty A, Bhola NE, Sutton C, Ghosh R, Kuba MG, Dave B, Chang JC, Arteaga CL. Trastuzumab-Resistant Cells Rely on a HER2-PI3K-FoxO-Survivin Axis and Are Sensitive to PI3K Inhibitors. Cancer ResFebruary 1, 2013 73; 1190. Published OnlineFirst November 29, 2012; doi: 10.1158/0008-5472.CAN-12-2440.
Photo courtesy ofVanderbilt-Ingram Cancer Center.
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