Abstract A169: Assessment of genotype-correlated sensitivity to the investigational PI3Kα selective inhibitor MLN1117 in preclinical models.
Authors: Iartchouk Natasha , Koenig Erik , Shah Pooja , Szwaya Jeff , Fitzgerald Michael , Zhang Dong Mei , Cao Yueying , Song Keli , Brake Rachael 
Published: August 2014

Abstract
The PI3K-Akt-mTOR signaling pathway is the most dysregulated pathway in cancer. Specifically, helical and kinase domain mutations in the p110α subunit (E542K, E545K, H1047R) account for greater than 15% mutations in many cancers. In addition, copy number gain of the PIK3CA locus (&gt;2.5 copies) also occur at a high frequency suggesting that these events are also associated with the oncogenic process. MLN1117 is an investigational PI3Kα selective inhibitor that is currently in Phase I dose escalation in subjects with advanced cancer (NCT01449370). It is widely hypothesized that PI3Kα isoform selective inhibitors will demonstrate considerable therapeutic benefit in PI3K “addicted” tumors; the work presented here is focused on identifying the association of genetic alterations with sensitivity to MLN1117. We have assessed the sensitivity profile both in vitro (n=47) and in vivo (n=29) using human tumor cell lines and primary human tumor xenografts, representing 9 different tumor types. PIK3CA gene point mutations are associated with sensitivity to MLN1117, in both in vitro and in vivo settings. 14 of 17 (82%) PIK3CA mutant cell lines demonstrate an in vitro IC50 of ≤ 5.0 μM and all non mutant models demonstrate an IC50 of &gt; 5.0 μM. In vivo 12 of 15 PIK3CA mutant models including two non-hotspot alterations (R88Q and G106_R108del) demonstrate a TGI value of &gt; 50%. Although copy number gain of PIK3CA is a frequent genetic event and could also be considered as a potential marker of sensitivity to PI3Kα inhibitors, in our assessment this was not apparent. We assessed 25 in vitro models and 16 in vivo models with a gain in the PIK3CA copy number greater than 2.5. Using a cut-off of IC50 of &lt;5μM and a TGI value of &gt;50% in both settings we did not identify a significant association between PIK3CA amplification and MLN1117 sensitivity. Thus, PIK3CA mutation status is a significant predictor in classifying sensitive vs. non-sensitive models to MLN1117 whereas PIK3CA copy number status is not (compare p=0.00002 vs p = 0.7668). Our assessment of models with PTEN alterations found all models to be insensitive to MLN1117 using our established in vitro criteria whereas several of these models were found to have borderline sensitivity (range 41-50% TGI) in vivo. These results suggest the need for additional exploration of the PTEN role and MLN1117 sensitivity. Additional trends observed in this data set are 1) PIK3CA co-mutated with KRAS is insensitive to MLN1117 in both in vitro and in vivo systems; and 2) complex mutations involving PIK3CA and ARID1A or EIF4B demonstrate a distribution of sensitivities. We present data that support the use of PIK3CA mutation as a patient selection strategy for clinical studies of MLN1117 while the utility of identifying patients with increases in PIK3CA copy number for clinical studies of MLN1117 may be limited.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A169.
Citation Format: Natasha Iartchouk, Erik Koenig, Pooja Shah, Jeff Szwaya, Michael Fitzgerald, Dong Mei Zhang, Yueying Cao, Keli Song, Rachael Brake. Assessment of genotype-correlated sensitivity to the investigational PI3Kα selective inhibitor MLN1117 in preclinical models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A169.