Large-Scale Genetic Profiling Technique Identifies Potential Weaknesses in Breast Cancer

Researchers at the Institute for Cancer Research (ICR) in London, driven by the unmet need of personalized cancer treatments for a greater subset of tumors have identified genes in breast tumor cells that sustain and grow the tumors that are potential targets for drug development. The data generated also allow for large-scale profiling which facilitated further subclassification of breast cancers distinct from current established subtypes.

Alan Ashworth, PhD and Christopher J. Lord, PhD see the project, whose first results were published online in Cancer Discovery on August 2, 2011, as a “first step toward the development of better treatments for the disease.” The authors joined Jos Baselga, MD, PhD, co-editor-in-chief of Cancer Discovery and chief of hematology/oncology at the Massachusetts General Hospital in a teleconference Tuesday to discuss the study and its results and implications.

The research is fueled by a movement towards better tumor characterization to develop tailored cancer treatments such as trastuzumab that has increased overall survival for women with HER2-positive breast cancer. Most cancers are still merely characterized as lacking specific mutations thus identifying a list of unsuitable treatments rather than effective ones.

“Our work really starts with the premise that cancer at a particular site is not a single disease rather it is multiple distinct diseases that have different prognoses and require treatments. In the past, treatments such as chemotherapy have been given on the basis of what is best for the average patient, rather than what is best for the individual patient,” stated professor Ashworth on the conference call.

“There has been a movement over the last few years toward individuated therapies for cancer where specific molecular changes within the tumor are identified and these are targeted, genes that are required for the cancer to thrive, and these have been the basis for the biggest advances in cancer treatments over the last few years,” he added.

The ICR researchers sought to mine the genetic alterations present in tumor cells to identify key “driver” mutations critical for sustaining tumor growth rather than “passenger” mutations that only reflect the vast genomic instability of the tumor cell environment. To address this issue, Ashworth and colleagues carried out a large function genetic screen in more than 30 breast cancer models to identify the driver mutations critical for a specific breast cancer subtype to grow.

“What we have attempted to do in this work is really to systematically catalog these mutations and to classify them functionally across the whole range of breast cancers using cells that we can grow in the lab,” explained Ashworth. “So really it’s like classifying motor cars by size or shape, or manufacturer, that’s what’s been done in the past. And what we started to do is to classify them by their engines so that we can aim to stop that engine from working using drugs.” 

The authors executed a “high-throughput RNA interference screen of a series of potentially drugable genes that generated comprehensive functional viability profiles for a range of commonly used breast cancer models. The research identified a dependency of PTEN-mutated breast tumor cells on mitotic checkpoint kinases, providing novel therapeutic targets to explore for this tumor subtype. The most significant dependency found for PTEN-mutated tumor cells was on the TTK protein kinase gene. The ICR researchers validated their hypothesis by showing that silencing TTK via siRNA silencing or chemical inhibition of the protein was selective for cells with a PTEN deficiency. Following up this work with more preclinical data on TTK inhibition may be a novel therapeutic strategy for PTEN-mutated cancers.

A potential target was also identified for estrogen-receptor positive cancers. “Our work matches decades worth of previous work. ER-positive breast cancer cell models are very sensitive to targeting of the ER receptor itself, but we found a novel gene, ADCK2. Targeting ADCK2 can also target this ER-positive subgroup of breast cancer. We don’t know the full mechanism but it provides at least a preliminary target,” commented Christopher J. Lord, the corresponding author and researcher at ICR.

“There are effective treatments for ER-positive disease, tamoxifen and inhibitors but unfortunately women do relapse from this disease and in fact more women with ER-positive disease die than women with ER-negative disease in total numbers, so it is still a problem that needs addressing,” added Ashworth.

The authors also underscored their technique as a broad approach applicable to most other cancers. “Our approach is scalable. We believe that we can do this for all genes and for all cancers,” Ashworth stated, highlighting not only the data set generated by this study, but the conceptual groundwork laid down for similar systematic approaches in other cancer types.

“This work is a starting point for these types of examples and that’s why we have made this data publicly available so that others can also try to work out where particular weaknesses are to target those,” stated Lord.

Dr. Baselga, professor at Harvard medical school, whose own laboratory focuses on the development of novel molecular targeted agents for breast cancers as well as other cancers, sees the work as transformational for the field of cancer therapeutic development. “The approach put forth in this paper could be totally game-changing for multiple reasons. I think that this approach is allowing us to identify therapies that are much more rational. For example, the work with the PTEN deficient cells that have identified these new kinases could be easily tied to the clinic and the same for the ER-positive work. So I am personally extremely excited. This is what we need to have a better understanding to find genes to target. I am personally extremely excited about this work when I saw it,” he stated during the teleconference.