Abstract 5588: Functional drug sensitivity and resistance profiling of AML patient cells defines a disease-specific combination of druggable signal addictions.

Abstract

Abstract Numerous underlying molecular events have been described in acute myeloid leukemia (AML), but still, the fundamental disease mechanisms are poorly understood. Several targeted therapies have been investigated for improved AML therapy but have not succeeded to date, likely due to the inability to identify the patient subgroups that are most likely to benefit. Here, we describe functional profiling of AML patient cells ex vivo with a drug sensitivity and resistance (DSRT) platform in order to distinguish disease- and patient-specific molecular vulnerabilities and individualized therapeutic strategies. The oncology drug collection covers 306 anti-cancer agents including 131 approved, 107 investigational and 68 experimental compounds. Each compound is tested in a dose response series allowing for calculation of drug sensitivity scores. The functional exploration of AML patient samples was accompanied with comprehensive molecular profiling and clinical background data to link drug sensitivities to molecular aberrations and predictive biomarkers. Comparison of the drug sensitivity profiles of 24 AML patient and 5 control samples revealed that targeted inhibitors often exhibit no to little effect in the controls and the majority of AML patient samples with only a subset of patients showing very selective responses, indicating that cancer specific vulnerabilities can be detected with the DSRT platform. Clustering of the drug responses among patient and control samples identified distinct subgroups of patients and drugs. Each of these groups could be defined by a separate drug class, implying that the linked samples were addicted to the corresponding signaling networks. Specifically, we saw select addictions to drug classes such as dasatinib/VEGFR TKIs, MEK inhibitors, rapalogs, JAK inhibitors, mTOR inhibitors in 6 (25 %), 5 (21%), 5 (21%), 5 (21%), and 6 (25%) of the patients, respectively. Together, these sensitivities highlight a set of disease-specific and individualized signaling nodes that can serve as starting points for personalized combination therapy strategies in AML. Further, integration of DSRT results with molecular and clinical profiling link some of the selective drug responses to clinically actionable markers. For example, dasatinib sensitivity was found to be predominant in AML M5 patients, suggesting that this drug is a promising therapeutic candidate for relapsed and refractory AML M5 patients. In conclusion, the DSRT platform can be used as a functional interrogation of patient cells leading to the identification of druggable vulnerabilities that can be used for personalized medicine strategies. Furthermore, insight into disease-specific signal addictions and establishment of how these are linked can aid in deconvoluting the complex molecular disease mechanisms of cancers and generate strategies for novel drug development. Citation Format: Tea Pemovska, Bhagwan Yadav, Riikka Karjalainen, Evgeny Kulesskiy, Mika Kontro, Muntasir Mamun Majumder, Laura Turunen, Ida Lindenschmidt, Anna Lehto, Jonathan Knowles, Caroline Heckman, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Krister Wennerberg. Functional drug sensitivity and resistance profiling of AML patient cells defines a disease-specific combination of druggable signal addictions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5588. doi:10.1158/1538-7445.AM2013-5588