Molecular mechanisms and pharmacological modulation of multidrug resistance protein 1 (MRP1) - drug resistance is a major barrier to effective cancer treatment

The National Cancer Institute awarded The Rockefeller University $100,228 on December 1, 2026, under the Cancer Research Manpower program (CFDA 93.398) to support research characterizing multidrug resistance protein 1 (MRP1) and developing MRP1-specific inhibitors to overcome chemoresistance in cancer patients.

The project addresses the role of MRP1 in exporting front-line cancer chemotherapeutics and its association with lower survival rates across multiple cancer types. The research comprises two primary aims: characterizing MRP1 in its native cell environment and conducting structure-based design of protein "minibinders" targeting the extracellular region of MRP1. The work targets an unmet need for MRP1-specific inhibitors with minimal off-target toxicity; prior clinical candidates failed due to cross-reactivity with other members of the multidrug resistance-associated protein family, which share high sequence similarity and overlapping substrates. MRP1-knockout mouse studies demonstrate that systemic MRP1 inhibition would be tolerated without developmental or reproductive defects, supporting the therapeutic potential of this approach.

Performance occurs in New York, New York, with a period of performance extending through May 31, 2028.

Although cancer therapies have become increasingly effective, many patients who experience initial remission will relapse due to chemoresistance. Drug resistance is estimated to account for 90% of treatment failures in patients with metastatic cancer. Therefore, addressing this major challenge remains a prerequisite for developing new cancer therapies. Multidrug transporters, such as multidrug resistance protein 1 (MRP1; ABCC1), play important roles in drug resistance by exporting several front-line cancer chemotherapeutics. MRP1 overexpression is strongly associated with lower survival rates in many cancers. Notably, MRP1-knockout mice do not exhibit defects in development or reproduction, suggesting that systemic inhibition of MRP1 would be tolerated. Inhibition of MRP1 is therefore an attractive therapeutic approach to prevent multidrug resistance. There is an unmet need for specific inhibitors of MRP1. Whereas several inhibitors have undergone clinical trials, all failed mainly due to off-target toxicity. Toxicity poses a serious challenge because MRP1 is one of nine members of the multidrug resistance-associated protein (MRP) family, which share high levels of sequence similarity, structural homology, and transports overlapping substrates. The other family members have various important physiological functions and are only rarely implicated in drug resistance. Consequently, an MRP1 inhibitor that cross-reacts with other mrps would cause unwanted toxicity. I hypothesize that by developing MRP1-specific inhibitors, we can prevent MRP-mediated drug resistance with minimal toxicity and enable novel cancer treatments. To test this hypothesis, i propose to characterize MRP1 in its native cell environment (aim 1) and to conduct structure-based design of protein "minibinders" of the extracellular region of MRP1 (AIM2). I hypothesize that characterizing MRP1 in its cell membrane environment will elucidate new structural attributes that inform its function. I will structurally characterize MRP1 in cell membrane-derived vesicles using cryoem. I will then compare this structure of MRP1 to previous detergent-solubilized structures of MRP1, as well as to other structures of MRP family members. Novel or unique structural components of MRP1 function can be harnessed for new approaches to alleviate MRP1-mediated multidrug resistance. Based on differing membrane localization of MRP family members and sequence divergence at their extracellular regions, i hypothesize that biologics that bind the extracellular region of MRP1 will achieve specificity while inhibiting substrate transport. In collaboration with DR. David baker's group, we have computationally designed "minibinders", proteins of 50 to 80 amino acids in length, targeting the extracellular region of MRP1. I will test these designs for binding affinity, specificity, and inhibition, and determine the binding mechanism of lead minibinders by cryoem. These minibinders would be the first drug-like molecules that bind the extracellular region of MRP1, providing a foundation for novel therapeutic approaches to targeting MRP1.