Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras

Abstract

SUMMARY The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins. Comparisons of differentially essential genes between Ras-dependent and -independent lines uncover synthetic lethal partners of oncogenic Ras. Screens in both human AML and engineered mouse pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling. Our findings suggest general strategies for defining mammalian gene networks and synthetic lethal interactions by exploiting the natural genetic and epigenetic diversity of human cancer cells.

Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens

“…We and others have observed that cancer cell lines exhibit highly variable genetic dependencies for cellular fitness (Bertomeu et al, 2018; Blomen et al, 2015; Hart et al, 2015; Hart et al, 2017a; McDonald et al, 2017; Meyers et al, 2017; Tsherniak et al, 2017; Wang et al, 2015; Wang et al, 2017b) in a manner that reflects the diverse genomic and transcriptomic alterations a cell may accumulate during tumorigenesis. Project Achilles (Broad Institute of MIT and Harvard) seeks to systematically map genetic vulnerabilities across large collections of cancer cell lines, including the Cancer Cell Line Encyclopedia (CCLE) (Barretina et al, 2012), and has recently performed genome-scale perturbation screens in 501 cancer cell lines using RNA interference (RNAi) (Tsherniak et al, 2017) and in 342 cancer cell lines using CRISPR-Cas9 (Meyers et al, 2017).…”

Atomic structure of the eukaryotic intramembrane RAS methyltransferase ICMT

“…ICMT is the only cellular enzyme known to methylate prenylcysteine substrates; methylation is important for their biological functions, including the membrane localisations and subsequent activities of Ras 1 , prelamin A 3 , and Rab 4 . ICMT inhibition has potential for combating progeria 3 and cancer 5–8 . Here we present an X-ray structure of ICMT, at 2.3 Å resolution, in complex with its cofactor, an ordered lipid molecule and a monobody inhibitor.…”

“…A recent study indicates that ICMT has a synthetic lethal interaction with oncogenic Ras 8 , suggesting possible efficacy of ICMT inhibitors for Ras-driven cancer. ICMT inhibitors may also have utility in treating progeria, the pathology of which is attributed to the accumulation of a prenylated and methylated form of prelamin A at the nuclear envelope 3,24 .…”

Pak2 regulates myeloid-derived suppressor cell development in mice

“…18 Pak kinases, as downstream effectors of Ras, are potential therapeutic targets in malignancies with hyperactive Ras, which account for ;30% of human cancers and are common in myeloid malignancies. [52][53][54][55] However, the reports that Pak2 depletion suppresses b-catenin activity 56 and downregulation of b-catenin promotes human MDSC activation and expansion in cancer 57 raise safety concerns regarding the pharmacological inhibition of group I Paks that target Pak1, Pak2, and Pak3. Our findings provide further evidence that the efficacy of targeting Paks may be undermined by tumor escape from immune control and/or acceleration of tumorigenesis through MDSC expansion.…”