By testing the effects of hundreds of genetic mutations found in cancer cells on their sensitivity to various established and experimental cancer drugs, the study also found several unpredicted associations between specific mutations and drug effectiveness, paving the way to more ‘personalised’ cancer therapy in the future.
Cancer is caused by faults in a cell’s genetic code, and these disrupt the cell’s normal control mechanisms for what it does, how big it grows or how it divides and multiplies. The effect is a mass of cells doing the wrong thing in the wrong place in a person’s body. The specific genetic mutations in the cancer determine how it progresses and, equally, how it responds to potential treatments.
Scientists from the Massachusetts General Hospital Cancer Centre and the Cancer Genome Project at the Wellcome Trust Sanger Institute are collaborating in a five-year programme to catalogue how cancer cells respond to different drugs depending on the precise genetic mutations they have.
The researchers took over 600 cell lines – populations of cells derived from real human cancers – and tested the effectiveness of 130 drugs against them. Their results showed that the power of most cancer drugs is influenced by the nature of the mutations in the cells being treated.
“Our work is helping to move cancer therapeutics away from the conventional tissue-based treatment to a more molecular-based treatment,” said Professor Daniel Haber, a senior author from the Massachusetts General Hospital Cancer Centre. “The next steps are to evaluate some of the key findings using tumour samples and test new candidate therapeutic strategies in clinical trials so we can hopefully improve the way we treat cancer patients.”
This will include studies to see if PARP inhibitors – drugs currently used to treat breast and ovarian cancers – also work for a bone cancer called Ewing’s sarcoma, which affects children and young people. The analysis showed a strong, unexpected association between a genetic mutation characteristic of Ewing’s sarcoma cells and sensitivity to a PARP inhibitor included in the assay.
The effectiveness of PARP inhibitors against Ewing’s sarcoma will now be tested in clinical trials: if successful, they could be a safer alternative treatment to current forms of therapy for this cancer.
Although it is crucially important to find such associations, where one mutated gene acts as a marker for how a patient’s cancer will respond to a particular drug, the study’s authors say that in most instances the sensitivity of cancer cells to specific drugs is likely to depend on several genetic factors and other variables. However, using high-throughput screening and next-generation genome sequencing will help us to understand the way these factors interact and guide future drug development.
The Sanger Institute’s Dr Matthew Garnett, first author on the research paper, said: “Our key focus is to find how to use cancer therapeutics in the most effective way by correctly targeting patients who are most likely to respond to a specific therapy.”
Image: A breast cancer cell. Credit: Anne Weston, LRI, CRUK, Wellcome Images.
Garnett et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012;483:570-5.