Phosphatidylinositol 3-Kinase Hyperactivation Results in Lapatinib Resistance that Is Reversed by the mTOR/Phosphatidylinositol 3-Kinase Inhibitor NVP-BEZ235

Abstract

Small molecule inhibitors of HER2 are clinically active in women with advanced HER2 positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach we performed a genome wide loss-of-function shRNA screen to identify novel modulators of resistance to lapatinib, a recently approved anti-HER2 tyrosine kinase inhibitor. Here, we have identified the tumour suppressor PTEN as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, we demonstrate that two dominant activating mutations in PIK3CA (E545K and H1047R), which are prevalent in breast cancer, also confer resistance to lapatinib. Furthermore, we show that PI3K induced lapatinib resistance can be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance which can be effectively reversed by NVP-BEZ235.

Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

“…Consistent with the known role for PI3K pathway activation in promoting resistance to HER2/neu inhibition (33,34), Lapatinib had only a mild effect in slowing tumor growth (Fig. 5A).…”

Understanding and circumventing resistance to anticancer monoclonal antibodies

“…71 Interestingly these factors are similar to those identified by a genome wide scan of factors involved in resistance to lapatinib, a small molecule inhibitor of HER2 tyrosine kinase. 72 These data also confirm previous results showing that PTEN is involved in sensitivity to trastuzumab. 73 …”

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

“…The data collectively indicate that AZD5363 has the potential to increase response or overcome resistance to HER2-targeting therapies in breast cancer. Other inhibitors of the PI3K/AKT/mTOR network have also been shown to increase the response or overcome resistance to HER2-targeting agents in breast cancer models (41,42). Interestingly, the HCC-1954 model, which is innately resistant to trastuzumab, expresses high levels of P95HER2, a truncated form of HER2 that lacks the extracellular ligand-binding domain.…”