Abstract
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.
Highlights
Extracellular matrix (ECM) proteins produced by diverse tumor types protect tumor cells from death in response to various agents.[3,4,5,6] Work from our laboratory and others in threedimensional (3D) culture systems has defined a protective role for ECM within the context of both normal[7] and tumor[1] cells
Using epithelial tumor cell lines cultured in reconstituted basement membrane (BM), we previously found that the outer, ECMattached cells are resistant to multiple different drug therapies.[1]
To address whether a similar differential adaptive response is observed in vivo, we examined a tumor model that recapitulates the ECM-enveloped architecture of 3D spheroids by generating ductal carcinoma in situ (DCIS)-like tumors via intraductal injection of HER2+ SUM225 breast tumor cells.[2]
Summary
Extracellular matrix (ECM) proteins produced by diverse tumor types protect tumor cells from death in response to various agents.[3,4,5,6] Work from our laboratory and others in threedimensional (3D) culture systems has defined a protective role for ECM within the context of both normal[7] and tumor[1] cells. Using epithelial tumor cell lines cultured in reconstituted basement membrane (BM), we previously found that the outer, ECMattached cells are resistant to multiple different drug therapies.[1] ECM protection involved activation of an adaptive response program, including FOXO-dependent transcriptional and capindependent translational induction of multiple receptor tyrosine kinases (RTKs) and pro-survival BCL2 family proteins. Since HER2+ DCIS accounts for 40–60% of all patient-related DCIS cases,[8,9,10,11,12,13] this model represents one of the most relevant approaches to understand the biology of HER2+ DCIS and to evaluate HER2-targeted therapies within the context of pre-neoplastic breast cancer
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