Using CRISPR-Cas9 to predict sensitivity to trastuzumab emtansine

Project Objective
Over 3000 diagnoses and 600 deaths are attributable to breast cancer in New Zealand each year. One-quarter of breast cancers is driven by increased amounts of a gene called HER2, which can be targeted with the drug trastuzumab (Herceptin). Trastuzumab markedly improves outcomes for HER2-positive breast cancer; unfortunately, treatment resistance develops in many patients, leading to poor prognosis. A new drug, trastuzumab emtansine (T-DM1 or Kadcyla), was recently approved for treating HER2-positive, metastatic breast cancer that has failed prior treatment with trastuzumab. However, T-DM1 shrinks tumours in only half of patients and the reasons why others are resistant remain unclear. This research uses a cutting-edge genetic tool –CRISPR-Cas9 – to identify genes that control (and thus predict) the sensitivity and resistance to T-DM1 in breast cancer. We aim to reduce the distressing uncertainty associated with treating this illness and to enable patients and their caregivers to make informed treatment decisions.

The study identified approximately 500 genes that may act in this way, with 14 that appear to have a very significant effect. We are now working with leading research institutions around the world to determine whether measuring the level of activity of these genes in tumour samples taken from breast cancer patients may enable us to predict whether each individual is likely to benefit from trastuzumab emtansine. In parallel, we are investigating whether our findings may help to inform better treatment of HER2-amplified breast cancer in such a way that avoids resistance to trastuzumab emtansine or ameliorates it if it does arise. 

HOST INVESTIGATOR: University of Auckland