Abstract LB-B07: MiSL: a method for mining synthetic lethal partners of somatic mutations identifies acetyl-CoA carboxylase as a synthetic lethal interactor of the IDH1 mutation in Leukemia
Authors: Sinha Subarna , Thomas Daniel , Gao Yang , Chan Steven M. , Brunen Diede , Bernards Rene , Majeti Ravindra , Dill David L. 
Published: May 2016

Abstract
Synthetic lethality, in which a single gene defect leads to dependency on a second gene that is otherwise not essential, is an attractive paradigm to identify targeted therapies for cancer-specific mutations. Current methods to detect synthetic lethal (SL) partners for somatic mutations rely on large-scale shRNA screens in cell-lines or use human orthologs of yeast SL interactions, both of which are not necessarily representative of primary tumors and have incomplete coverage.
We have developed MiSL, a novel Boolean implication-based algorithm that utilizes large pan-cancer patient datasets (mutation, copy number and gene expression) to identify SL partners for cancer mutations. The underlying assumption of our approach is that, across multiple cancers, SL partners of a mutation will be amplified more frequently or deleted less frequently, with concordant changes in expression, in primary tumor samples harboring the mutation. Pan-cancer analysis discovers robust biological relationships that are likely to be independent of cancer subtype and increases statistical power.
First, we sought to validate MiSL using existing knowledge and large-scale shRNA data. Consistent with prior knowledge, MiSL candidates for BRCA1 mutation (mut) in breast cancer were enriched for DNA repair genes (p = .0.006). We also found: (1) significant overlap (p = 0.002) between leukemia IDH1mut MiSL candidates and essential genes in IDH1mut cells determined by a DECIPHER shRNA screen we performed in doxycycline-inducible IDH1 (R132) THP-1 cells, and (2) for multiple mutations in colorectal cancer, MiSL candidates were enriched (p&lt;0.05) with genes that were selectively essential in mutated colorectal cell-lines in Achilles data.
Next, we experimentally confirmed novel SL partners that are druggable in (i) acute myeloid leukemia (AML) and (ii) breast cancer. We tested the response to 17 drugs whose targets were predicted to be SL partners of IDH1mut in AML by MiSL. For a majority of these drugs, treatment with the drug reduced cell viability selectively in the presence of the mutation in AML cell-lines, suggesting that the MiSL identifies true SL partners. Importantly, MiSL predicted a novel SL interaction in AML between IDH1mut and ACACA, the rate-limiting enzyme that controls lipid biosynthesis. Consistent with our prediction, selective inhibition of ACACA with shRNA or a small molecule inhibitor TOFA prevented cell proliferation in the presence of IDH1mut but not with IDH1 wildtype in AML cell-lines and primary blasts (n = 5/6 IDH1mut/IDH1 wt, p = 0.04). This suggests a novel role for IDH1mut in reprogramming lipid metabolism. MiSL also predicted that AKT1 is a SL partner of PIK3CAmut in breast cancer which we experimentally confirmed using 8 breast cancer lines. All four PIK3CAmut (but not wildtype) breast cancers were sensitive to AKT1 inhibition in viability and colony assays.
In conclusion, MiSL is a general computational solution that finds novel SL interactions and its use can greatly accelerate novel target discovery for precision medicine in cancer. Using primary patient data allows it to capture in vivo tumor evolution in the human microenvironment, revealing SL interactions missed by existing methods. It can be widely applicable and can greatly accelerate novel target discovery for precision medicine in cancer.
Citation Format: Subarna Sinha, Daniel Thomas, Yang Gao, Steven M. Chan, Diede Brunen, Rene Bernards, Ravindra Majeti, David L. Dill. MiSL: a method for mining synthetic lethal partners of somatic mutations identifies acetyl-CoA carboxylase as a synthetic lethal interactor of the IDH1 mutation in Leukemia. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B07.