Environmental-mediated drug-resistance (EM-DR) presents a major challenge for therapeutic development. Tissue microenvironment in the form of extracellular matrix, soluble factors, and stroma contribute to EM-DR. In multiple myeloma (MM), drug-resistance has hindered treatment success with 5-year survival rates remaining <50%. Here we evaluated IMGN901, a maytansinoid immunoconjugate, for its ability to overcome EM-DR alone or in combination with lenalidomide or dexamethasone. We show that while adhesion of MM cells to the extracellular matrix reduces potency of IMGN901, it remains cytotoxic with an average LC50=43 nM. However, only a combination of IMGN901, lenalidomide, and dexamethasone was able to overcome drug-resistance arising from the direct contact between MM and stromal cells. We demonstrate that multi-drug resistance protein-1 (MDR-1) was upregulated in MM cells grown in contact with stroma, likely responsible for the observed resistance. This study emphasizes the importance of incorporating the elements of tumor microenvironment during preclinical testing of novel therapeutics.
Keywords: MDR-1; Multiple myeloma; environment-mediated drug resistance; extracellular matrix; tumor-stromal interactions.