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Despite the success of antiestrogens in extending overall survival of patients with estrogen receptor positive (ER+) breast tumors, resistance to these therapies is prevalent. ER+ tumors that progress on antiestrogens are treated with antiestrogens and CDK4/6 inhibitors. However, 20% of these tumors never respond to CDK4/6 inhibitors due to intrinsic resistance. Here, we used endocrine sensitive ER+ MCF7 and T47D breast cancer cells to generate long-term estrogen deprived (LTED) endocrine resistant cells that are intrinsically resistant to CDK4/6 inhibitors. Since treatment with antiestrogens arrests cells in the G1 phase of the cell cycle, we hypothesized that a defective G1 checkpoint allows resistant cells to escape this arrest but increases their dependency on G2 checkpoint for DNA repair and growth, and hence, targeting the G2 checkpoint will induce cell death. Indeed, inhibition of WEE1, a crucial G2 checkpoint regulator, with AZD1775 (Adavosertib), significantly decreased cell proliferation and increased G2/M arrest, apoptosis and gamma-H2AX levels (a marker for DNA double stranded breaks) in resistant cells compared with sensitive cells. Thus, targeting WEE1 is a promising anti-cancer therapeutic strategy in standard therapy resistant ER+ breast cancer.

17Resistance to endocrine therapies remains a major challenge for the successful 18 management of patients with estrogen receptor-positive (ER+) breast cancers. Central to 19 the development of resistance is the adaptive reprogramming of cellular metabolism in 20 response to treatment. Solute carriers (SLCs) play a key role in metabolic reprogramming 21 by transporting sugars, amino acids, and other nutrients and regulating their abundance 22 within the cell and its subcellular organelles. We found 109 SLC mRNAs to be 23 differentially expressed between endocrine sensitive and resistant breast cancer cells. In 24 univariate analyses, 55 of these SLCs were associated with poor outcome in ER+ breast 25 cancer patients. Data from TMT and SILAC studies then led us to focus on SLC7A5 26 (LAT1). In complex with SLC3A2 (CD98), LAT1 is the primary transporter of large, neutral 27 amino acids including leucine and tyrosine. LAT1 expression is estrogen-regulated in 28 endocrine sensitive cells but this regulation is lost in resistant cells. Pharmacologic 29 inhibition or genetic depletion of LAT1 each suppressed growth in two models of 30 endocrine resistant breast cancer. Autophagy was activated with LAT1 inhibition, but cells 31 failed to degrade p62 showing that flux was blocked. Overexpression of the LAT1 cDNA 32 increased protein synthesis and high LAT1 expression correlated with poor disease-free 33 survival in ER+ breast cancer patients. This study uncovers a novel LAT1 mediated 34 adaptive response that contributes to the development of endocrine resistance. Blocking 35 LAT1 function may offer a new avenue for effective therapeutic intervention against 36 endocrine resistant ER+ breast cancers.37 38 Introduction: 39 In the United States, breast cancer is the most commonly diagnosed cancer in 40 women 1 . Of the 253,000 newly diagnosed breast cancers each year, approximately 70% 41 are estrogen receptor positive (ER+) 2 . Endocrine therapies, such as aromatase inhibitors 42 (AIs) and selective estrogen receptor modulators (SERMs), have extended life 43 expectancy for patients with ER+ disease 3 . Unfortunately, resistance to these treatments 44 is common 4,5 . Patients who do not initially respond to endocrine therapies (de novo 45 resistance), or who initially respond but eventually recur (acquired resistance), generally 46 require cytotoxic chemotherapies. Chemotherapy often induces serious side effects 6 but 47 is rarely curative in advanced disease. It is critical to understand how resistance to 48 endocrine therapy develops and to design more effective treatments for patients. Ideally, 49 this can be achieved while minimizing toxicity. 50 Dysregulation of cellular energetics, a key hallmark of cancer, is driven by altered 51 metabolism in cancer cells compared with normal cells 7,8 . Unique aspects of cancer cell 52 metabolism can use pro-survival mechanisms, such as autophagy, to survive under 53 stress or in a nutrient-poor microenvironment. Autophagy is an intracellular process of 54 lysosomal degradat...

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