Cancer is a heterogeneous disease, with myriad distinct subtypes that
differ in their genetic roots. As a result, cancers rely on varied
pathways for survival - and respond differently to anticancer agents.
challenge for researchers is to precisely define those diverse pathways
and pinpoint vulnerabilities that may serve as drug targets for new
‘By combining the "gene essentiality map" with the existing genomic information of acute myeloid leukemia, the researchers revealed liabilities in genetically defined subset of cancers that could be exploited for new therapies.’
Investigators at Whitehead Institute and the Broad Institute have
taken an important step in tackling that challenge: They have succeeded
in identifying the set of essential genes - those required for cellular
proliferation and survival - in each of 14 human acute myeloid leukemia
(AML) cell lines that had previously been characterized by genome
By combining their "gene essentiality map" with the existing
genomic information, their study revealed liabilities in genetically
defined subset of cancers that could be exploited for new therapies.
The report on their work, appearing in the online edition of Cell
, is entitled, Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras.
A major aspect of the study focuses on the genes and protein
pathways connected to the Ras oncogene, the most commonly mutated
oncogene in human cancers which plays a role in AML as well as many
other cancers. "For the most part, the mutant Ras protein itself has
been considered to be 'undruggable'," explain Tim Wang, the paper's
first author and an MIT graduate student researcher at Whitehead
Institute and the Broad Institute.
"An alternative approach has been to
find other genes that Ras-mutant cancers rely on with the hope that one
of them may be druggable. Unfortunately, such 'Ras-synthetic-lethal'
genes have been difficult to identify." notes Wang.
Using CRISPR-based gene editing technique, the researchers could
gauge the impact of individually knocking out each of the 18,000
protein-coding genes in the human genome. "This process rapidly enabled
us to identify the short list of genes that were selectively required in
only the Ras-mutant cells," explained David Sabatini, a senior author
on the paper, as well as a Member of the Whitehead Institute, Pprofessor
of Biology at MIT, and an investigator of the Howard Hughes Medical
Institute. "We think this general approach can be applied to find
vulnerabilities in many more cancer types."
In addition to defining the Ras-specific gene essentiality network,
the data generated from this study also allowed the researchers to
decipher the molecule function of previously unstudied genes. They
started by focusing in on genes that were essential in some of the cell
lines but dispensable for others. For each of these genes, the
researcher sifted through their data to find others that showed a
matching pattern of essentiality with the idea that all of them had
similar functions. Indeed, this 'guilt-by-association' analysis revealed
gene groups that were already known to act together and uncovered novel
associations between genes that were not known to be related or had
been previously unstudied.
"What's particularly exciting about this work is that we have just
begun to scratch the surface with our method," Wang concludes. "By
applying it broadly, we could reveal a huge amount of information about
the functional organization of human genes and their roles in many