The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating <i>PIK3CA</i> mutations.
Since PI3K inhibition does not only affect the metastatic cells but also re-educates the metastasis-promoting macrophages/microglia, PI3K inhibition may hold considerable promise in the treatment of brain metastasis and the respective microenvironment.
HER3 blockade overcame the resistance of <i>HER2</i>-amplified and/or <i>PIK3CA</i>-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival.
Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases.
We performed next-generation sequencing of metastatic SQCLCs and primary lung-brain metastasis pairs, identifying PI3K-aberrant tumors as an aggressive subset associated with brain metastases.
In analysis of individual SNPs, the GT/GG genotype of AKT1: rs2498804, CT/TT genotype of AKT1: rs2494732, and AG/AA genotype of PIK3CA: rs2699887 were associated with higher risk of brain metastasis at 24-month follow-up [respective HRs, 1.860, 95% confidence interval (CI) 1.199-2.885, P = 0.006; HR 1.902, 95% CI 1.259-2.875, P = 0.002; and HR 1.933, 95% CI 1.168-3.200, P = 0.010].
Thus, inhibition of PI3K-AKT signaling shows potential for enhancing and/or prolonging the antitumor effect of BRAF inhibitors or other anticancer agents in melanoma brain metastases.