Abstract P1-17-02: Adaptive and acquired mechanisms of resistance to PI3K inhibitors
Authors: Sarat Chandarlapaty, Maurizio Scaltriti, Marie Will, Zhiqiang Li, Ana Bosch-Campos, Sarit Schwartz, Vanessa Rodrik-Outmezguine, Michael Berger, Baselga Jose, Neal Rosen
Journal: Cancer Research (2015)

Abstract Background: Activation of PI3K alpha is among the most frequent oncogenic events in breast transformation, commonly occurring through mutations in the p110 alpha subunit of PI3K or amplification of the HER2 receptor tyrosine kinase. Therapeutic targeting of activated PI3K signaling has been made feasible by the development of highly selective and potent ATP competitive inhibitors of p110 alpha some of which are in late stage clinical development. Unfortunately, clinical response to these compounds has not been seen for the majority of patients and when response occurs it is often short-lived. We have hypothesized that relief of feedback regulation of PI3K signaling constitutes a major mechanism for tumor cell adaptation to inhibitors of oncogenes such as PI3K. Methods: To understand the basis for resistance to PI3K inhibitors we studied the consequences of acute and prolonged PI3K inhibition in patient samples as well as in cell line and murine models of breast cancer. We examined the effects of selective inhibition of PI3K alpha on upstream and parallel signaling pathway components utilizing several phosphoproteomic methods including mass spectrometry, antibody microarrays, and immunoblotting. We further investigated the consequences of PI3K inhibition upon the genome using next generation sequencing. Results: In the context of tumors with high levels of RTK signaling such as HER2+ breast cancers, inhibitors of PI3K alpha led to only transient inhibition of PI3K/AKT signaling with reactivation of signaling closely coinciding in time with loss of feedback suppression of RTKs such as HER3 and IGF1R. This reactivation of AKT signaling could be blocked using inhibitors of the induced RTKs and this was associated with a marked increase in tumor cell death. A second mechanism of reactivation of PI3K signaling was observed in examining the genomes of tumors where inhibition of PI3K alpha was associated with acquired inactivating mutations in PTEN. Loss of PTEN in such tumors was associated with failure of the PI3K alpha inhibitor to block PI3K/AKT signaling but sensitivity to combined PI3K alpha plus PI3K beta inhibition in laboratory models. Finally, in the context of hormone dependent tumor models, inhibition of PI3K alpha was associated with an increase in estrogen receptor activation. This was observed as increases in ER protein expression, ER phosphorylation, and ER binding to established ER target promoters. Combined inhibition of ER and PI3K alpha was demonstrated to be synergistic in these models in vivo. Conclusions: Feedback suppression of upstream and parallel signaling pathways poses a major limitation to the antitumor effects of single agent PI3K alpha inhibition. Combination approaches to potently inhibit PI3K alpha, PI3K beta, and either ER or HER3/IGF1R may prove more effective and durable in the clinic. Citation Format: Sarat Chandarlapaty, Maurizio Scaltriti, Marie Will, Zhiqiang Li, Ana Bosch-Campos, Sarit Schwartz, Vanessa Rodrik-Outmezguine, Michael Berger, Baselga Jose, Neal Rosen. Adaptive and acquired mechanisms of resistance to PI3K inhibitors [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-17-02.