Dual PI3K/mTORC1 Targeting Suppresses HER2⁺ Brain Metastasis Xenografts

In patients with HER2⁺ breast cancer, metastasis to the brain is a major clinical challenge. To discover targeted therapies, Ni, Ramkissoon, Xie, and colleagues developed orthotopic patient-derived xenografts (PDX) of HER2⁺ breast cancer brain metastases (BCBM) from 5 patients with BCBMs. An initial PDX exhibited resistance to the HER2 inhibitor lapatinib, and PTEN loss, which occurs in many BCBMs and is expected to activate PI3K signaling. However, there was no response to lapatinib plus the PI3K inhibitor BKM120. AKT and mTOR are downstream of PI3K, and although BKM120 plus lapatinib reduced AKT phosphorylation, phosphorylation of the mTOR effector S6RP was unchanged. In breast cancer, mTOR activity has been shown to mediate PI3K inhibitor resistance, which can be overcome by mTORC1 inhibition. However, it is not known if mTORC1 inhibition is effective in brain metastases, which are often refractory to systemic treatment. Combined inhibition of PI3K with BKM120 and mTORC1 with RAD001 resulted in tumor regression, whereas the single agents had little effect. Combination therapy with BKM120 and RAD001 induced durable tumor regression in 3 of 5 PDXs, with mice remaining healthy after treatment cessation. While single-agent therapy with BKM120 or RAD001 reduced mTORC1 signaling, combined therapy completely inhibited mTORC1 and also reduced proliferation and enhanced apoptosis. Transcriptome analysis of BCBMs from mice showed that responding tumors exhibited increased expression of AKT/mTOR-dependent genes. Moreover, whereas the responding BCBMs had a nonsynonymous somatic mutation rate of approximately 7–8 per Mb, nonresponding BCBMs exhibited approximately 60–70 mutations per Mb, including mutations in multiple DNA-repair genes. This suggests that hypermutated genomes and genomic instability promoted resistance. Altogether, these findings suggest clinical evaluation of BKM120 and RAD001, a combination already under clinical investigation in solid tumors, is warranted in patients with HER2⁺ BCBMs. Further, this study demonstrates the utility of brain metastasis PDX models for identification of targeted therapies.

Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, et al. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 2016;22:723–6.

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