Niche-localized tumor cells are protected from HER2-targeted therapy via upregulation of an anti-apoptotic program in vivo

Several lines of evidence suggest that components of the tumor microenvironment, specifically basement membrane and extracellular matrix proteins, influence drug sensitivities. We previously reported differential drug sensitivity of tumor cells localized adjacent to laminin-rich extracellular matrix in three-dimensional tumor spheroid cultures. To evaluate whether differential intra-tumor responses to targeted therapy occur in vivo, we examined the sensitivity of human epidermal growth factor receptor 2-positive tumors to lapatinib using a previously described ductal carcinoma in situ-like model characterized by tumor cell confinement within ductal structures surrounded by an organized basement membrane. Here we show that tumor cells localized to a ‘niche’ in the outer layer of the intraductal tumors adjacent to myoepithelial cells and basement membrane are resistant to lapatinib. We found that the pro-survival protein BCL2 is selectively induced in the niche-protected tumor cells following lapatinib treatment, and combined inhibition of HER2 and BCL-2/XL enhanced targeting of these residual tumor cells. Elimination of the niche-protected tumor cells was achieved with the HER2 antibody–drug conjugate T-DM1, which delivers a chemotherapeutic payload. Thus, these studies provide evidence that subpopulations of tumor cells within specific microenvironmental niches can adapt to inhibition of critical oncogenic pathways, and furthermore reveal effective strategies to eliminate these resistant subpopulations. Drug resistance: Overcoming localized resistance to anti-HER2 therapy Location-specific subpopulations of breast cancer cells adapt to targeted drug treatment, but therapeutic strategies exist to attack these niche-protected cells. A team led by Joan Brugge and Jason Zoeller from Harvard Medical School, USA, implanted human HER2+ breast tumor cells into the ducts of mouse mammary glands to recapitulate the architecture of ductal carcinoma in situ, a common type of non-invasive breast cancer. They found that cancer cells located on the outer rim of the tumors were resistant to lapatinib, a drug that targets the HER2 protein. Combination treatment with lapatinib and a drug that blocks a pro-survival protein called BCL2 that was specifically enriched in the outer cells after lapatinib treatment helped kill more cells. Complete elimination of the resistant cells was achieved with an antibody-drug conjugate, T-DM1, that binds to HER2 and then releases a chemothe