In a phase I study, the combination of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus displayed anti-tumor activity in patients with HER2+ breast cancer resistant to trastuzumab, HER2-mutant non-small cell lung cancer, and tumors without identified mutations in the HER-PI3K-mTOR pathway [246]. This evidence concerns the gene PIK3CA and breast carcinoma.