Abstract 23: Using mutations in mismatch repair genes to predict response to palbociclib
Authors: Aloran Mazumder, Nindo Punturi, Sujita Khanal, Athena Jimenez, Svasti Haricharan
Journal: Clinical Cancer Research (2020)

Abstract Over 175,000 diagnoses of estrogen receptor-positive breast cancer are made every year in the US. Of these, &amp;gt;40,000 patients will go on to die of their disease. We recently identified defects in a principal mismatch repair (MMR) gene, MLH1, as a driver of resistance to standard-care treatment and poor patient outcomes. Moreover, we demonstrated increased sensitivity to palbociclib, a CDK4/6 inhibitor, in experimental model systems in vitro and in vivo and in clinical trial data. MLH1 is mutated in 5-10% of treatment-resistant tumors, i.e., 4,000 patient tumors every year. However, most of these mutations are missense and variants of unknown significance (VUS). The impact of these mutations on mismatch repair capability and on treatment resistance remains uncertain. Here, we use experimental model systems (MCF7 cells and a PDX mode, WHIM20) to phenotype MLH1 VUS´ in vitro and in vivo using xenograft systems. Specifically, we use nuclear localization of MLH1 and repair of mismatches through a mismatch repair deficiency assay to test for mismatch repair capability in ER+ breast cancer cells engineered to express mutations in MLH1 that are found in patient tumors associated with poor survival. Second, we assess the ability of variants of MLH1 to induce activation of G1/S cell cycle checkpoints by activating Chk2. Lastly, we directly test the ability of variants in MLH1 to induce resistance to standard-care endocrine therapies and sensitivity to palbociclib, using 2D and 3D growth assays and xenograft experiments. Results from these experiments serve to systematically catalog VUS´ in MLH1 based on their predictive potential. Currently, there are few tests available in the clinic to predict response to therapies early in the timeline of ER+ breast cancer patients. Due to the nature of the disease, this can result in years of overtreatment. Overtreatment comes at great financial, physical, and emotional cost to patients and their families. Simultaneously, a lack of predictive markers can result in missed opportunities of presenting patients likely to relapse on standard care with personalized alternative therapeutic strategies. With the increased feasibility of sequencing patient tumors in the clinic, there is a large gap in knowledge regarding the impact of VUS´ in various oncogenes on disease progression and treatment response. Data presented here address this gap by cataloging the impact of a range of VUS´ from patient tumors on protein localization and function, as well as macrophenotypes of tumor growth and therapeutic response. Note: This abstract was not presented at the conference. Citation Format: Aloran Mazumder, Nindo Punturi, Sujita Khanal, Athena Jimenez, Svasti Haricharan. Using mutations in mismatch repair genes to predict response to palbociclib [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 23.