A large-scale project in genetic profiling has identified weak points in breast tumor cells that not only represent potentially new “druggable” targets but could lead to an entirely new classification of all cancers. The findings were recently reported in Cancer Discovery, a journal of the American Association for Cancer Research,1 and were the topic of a teleconference moderated by Jose Baselga, MD, PhD, Co-Editor-in-Chief of the journal and Chief of Hematology/Oncology at the Massachusetts General Hospital.
“My own work as been in the development of new therapies in breast cancer. I can say that the approach put forward in this paper could be totally game-changing,” Dr. Baselga commented during the briefing.
“Despite the wealth of molecular profiling data that describe breast tumors, our understanding of the fundamental genetic dependencies in this disease is relatively poor,” the investigators noted. The group, therefore, was interested in deciphering not just the location and structure of genetic mutations but the “functional viability” of the mutations as well.
“Previous classification with genomics has made headway, but it catalogs structure over the activity of genes. Many alterations are not critical for the cancer cell’s survival. They are not ‘drivers.’ We classified tumors by what drives them,” explained Alan Ashworth, PhD, lead author, of the Institute for Cancer Research in London.
How Functional Screening Is Done
Dr. Ashworth and colleagues performed high-throughput RNA interference screening on 34 breast cancer cell lines to identify a series of genes upon which breast cancer cells rely, ie, the novel “genetic dependencies” for “druggable” genes.
Ultimately, the research team identified 330 genes whose depletion by small interfering RNA caused loss of viability in at least one cell line and 180 genes that caused loss of viability in two or more lines. This analysis enabled the investigators to identify the predominant dependencies in each cell line.
They ultimately selected 20 breast cancer cell lines, encapsulating the major breast cancer subtypes, for subsequent interrogation. The tumor panel was further characterized by means of transcript microarrays, array-based comparative genomic hybridization, drug sensitivities for several targeted agents, and gene mutation data.
The investigators were able to validate known targets such as ERBB2 (HER2) and PIK3CA and to identify potential new therapeutic targets, including the TTK protein kinase gene for PTEN-mutated cancers. A number of oral TTK inhibitors that target PTEN deficiency are now in development.
They also showed that ADCK2 silencing is selectively lethal in estrogen receptor (ER)-positive tumor cell lines and that ADCK2 inhibition abrogates estrogen signaling. Although there are no ADCK2 inhibitors in development yet, this finding could lead to non–endocrine-based treatments for ER-positive disease.
These are just examples of the multiple vulnerabilities that can be exploited, the investigators noted. “We need to find the weaknesses in breast cancer cells and then develop drugs that hit these weak spots. With this new information we can start to do that,” said coauthor Christopher Lord, PhD, also of the Institute for Cancer Research.
Could All Cancers Ultimately Be Reclassified?
“We showed that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from the established subtypes,” Dr. Ashworth said.
Another participant in the teleconference, Rene Bernards, PhD, Professor of Molecular Carcinogenesis at The Netherlands Cancer Institute in Amsterdam, added that this study lays the groundwork for discerning critical genetic profiles within a single patient’s cancer. “The investigators are making a systematic map showing the specific vulnerabilities of cancer cells with mutations in their genome. There are correlations between the mutations and their vulnerabilities. We can begin to target them where the effect will be the greatest, …and this will lead to improvements in survival,” he predicted.
Dr. Baselga questioned whether this groundbreaking work might lead to a new classification of breast cancer based on functional categories, not histologic subtypes.
“Historically, we have categorized cancer by tissue of origin,” Dr. Bernards responded. “The significance of the current study is that we now appreciate we should begin to call cancers by the oncogenic driving lesion responsible for malignant growth… and initiate treatment based on this driver.”
According to Dr. Ashworth, this is indeed the likely direction of research. “I envision a future where a panoply of genes will be studied for mutations, and it will be tremendously informative for treatment,” he said. Stand Up to Cancer provided funding for this research, added Dr. Ashworth, who is a principal on the Breast Cancer Subtypes Dream Team. ■
Disclosure: Drs. Baselga, Bernards, and Lord disclosed no potential conflicts of interest.
1. Brough R, Frankum JR, Sims D, et al: Functional viability profiles of breast cancer. Cancer Discovery. August 2, 2011 (early release online).