Although many treatment advances in breast cancer have been made, resistance inevitably develops. Activating mutations in PIK3CA that occur in patients with HER2 amplification can often confer resistance to anti-HER2 therapies. Using the SNaPshot assay, researchers have idenitifed 'hotspot' PIK3CA mutations in cells resistant to the HER2 inhibitor lapatinib. They showed that the PIK3CA mutations partially uncouple PI3K signalling from HER2, and that resistance could be overcome by using the pan-PI3K inhibitor BKM120. In mice with HER2-amplified tumours, dual HER2 blockade with trastuzumab and lapatinib resulted in tumour regression, and the addition of BMK120 further improved tumour regression. The combination of PI3K inhibition with dual HER2 blockage seems to circumvent resistance to HER2 inhibitors, providing a rationale to further explore this strategy.
References
Rexer, B. N. et al. Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells. Breast Cancer Res. 10.1186/bcr3601
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Overcoming resistance with dual HER2 blockade. Nat Rev Clin Oncol 11, 123 (2014). https://doi.org/10.1038/nrclinonc.2014.22
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DOI: https://doi.org/10.1038/nrclinonc.2014.22
