Can cancer cells’ “addiction” to a specific oncogene be exploited to develop new therapies? Coined by Bernard Weinstein, M.D., Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, oncogene addiction refers to the apparent dependence of a cancer cell on one overactive gene or pathway for its growth and survival.
Dr. Weinstein suggested the concept of oncogene addiction in 1997, after observing that only partially blocking cyclin D1, a protein required for cell division, was enough to arrest the growth of cancer cells overexpressing the protein.
Oncogene addiction has provided a rationale for molecular-targeted therapy. But, as Dr. Weinstein noted, ferreting out addiction pathways and either combining older drugs or designing new ones to exploit them requires novel methods, including integrative genomics and systems biology, to identify the state of oncogene addiction (i.e., the Achilles’ heel) in specific cancers.
Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets.
But is this phenomenon transferrable to human tumors, and how useful is it in discovering new therapeutics for intractable cancers? Oncogene addiction thus far remains a phenomenon observed in the laboratory, and whether most human tumors are oncogene addicts remains unknown, despite the isolated successes of targeted therapies like imatinib (Gleevec) that targets bcr-abl. “Molecular targeting relies on the assumption that, amidst all the chaos in the tumor, there are one or a few molecular targets that are very critical,” Weinstein said.
But large scientific enterprises are bearing down on some of these questions with the array of technologies that Dr. Weinstein suggested would be required to determine whether oncogene addiction is a real, exploitable phenomenon, discoverable in a consistent way, as well as providing some of these tools.
Last June, the American Association of Cancer Research (AACR) organized a meeting entitled "Chemical Systems Biology: Assembling and Interrogating Computational Models of the Cancer Cell by Chemical Perturbations."
Now, for the first time, the conference chairs said, scientists can interrogate genome-wide models to identify candidate genes. Modulation of these genes using the tools of chemical biology may well, they say, derail tumorigenesis, target key oncogene and nononcogene addiction mechanisms, and rescue sensitivity to chemotherapy.
Meeting organizers said that the intersection of chemical biology and systems biology will allow unprecedented leaps in understanding how cancer cells work.
The Harvard/MIT-based Broad Institute, as part of the National Cancer Institute’s Cancer Target Discovery and Development (CTD2), says small chemical probes, small molecules designed to interrogate cellular pathways of interest, are key to furthering chemical biology. And key among those programs, the institute says, is its mission to decode cancer genotypes so as to read out acquired pathway and oncogene addictions of the specific tumor subtypes, and to identify small molecules that target these dependencies.
As part of the institute’s mission Broad scientists are assembling an "Acquired Cancer Dependency Probe Kit" of new and existing small molecule probes whose members modulate many candidate targets/processes shown to play a role in cancer. Scientists are using this probe kit in screens of ~500 cell lines with characterized genotypes to identify the dependencies associated with a given cancer genotype and make them available to the scientific community.
Cataloging these Achilles’ heels and linking them to the causal genetic alterations, the institute says, will be critically important for therapies that are personalized to individual patients, including combination therapies aimed at targeting multiple dependencies at once.
Acute Myeloid Leukemia
And using all of the tools cited above, substantive gains in understanding mechanisms of oncogene addiction are beginning to accumulate. Last July, a team of scientists at Cold Spring Harbor Laboratory (CSHL) reported that they had characterized cellular programs associated with oncogene addiction in a mouse model of human acute myeloid leukemia.
Using genetically defined mouse models, transcriptional profiling, and an inducible RNAi platform, the investigators identified the cellular programs underlying the recognized addiction of leukemia cells to the fusion protein MLL-AF9, an oncoprotein associated with particularly aggressive forms of the disease in humans.
The investigators working in the laboratory of CSHL adjunct professor and HHMI investigator Scott W. Lowe, who directed the research, showed that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential as well as poor prognosis in human AML.
To build their mouse models, the investigators introduced common human AML mutations in the animals, creating mosaic mice that mimicked human AML in symptomatology and treatment responses. Among the genes introduced into the mice was the gene giving rise to the “addictive” MLL-AF9 oncoprotein.
The investigators were able to inactivate the gene in the mice via a genetic switch. In the MLL-AF9–suppressed mice, tumors shrank and were eliminated from affected organs. This result, the investigators said, confirmed the cancer cells’ addiction to MLL-AF9 and provided a unique system to reveal the underlying genetic networks.
By combining approaches integrating mouse cancer models, transcriptional profiling, and inducible RNAi to systematically select and test candidate mediators of oncogene addiction in vivo, the authors identified Myb as a central mediator of oncogene addiction in AML. They further showed that its suppression eradicates aggressive leukemia in vivo without impacting normal myelopoiesis.
Additionally, and importantly, they could identify key Myb effectors that coordinate the addiction program, which could potentially serve as targets for small molecule inhibitors. Similar approaches can be used to systematically identify and validate tumor maintenance genes in other cancer models.
“MLL-AF9 apparently ‘hijacks’ Myb to enforce a program of aberrant self-renewal,” explained Amy Rappaport, who was a co-first author on the paper with Johannes Zuber. “The consequences of inhibiting Myb in established leukemia were striking,” Dr. Zuber commented. “Following Myb suppression, mouse leukemia cells invariably lost their aberrant self-renewal ability, resumed their normal cell fate, [matured] into white blood cells, and eventually got eliminated.”
But, other scientists say, while in vitro and in vivo examples “abound,” documentation of the existence of oncogene addiction and its mechanistic underpinnings is just beginning to emerge. At the same time, they believe that, despite current limited understanding of this phenomenon, it may represent one of the rare gaps in cancer cells’ formidable defense.