Exploring LMTK2: A novel mediator of endocrine sensitivity in ER+ breast cancer

About This Grant

PROJECT SUMMARY Breast cancer is the second most common female malignancy and the second leading cause of cancer regardless of sex in the world. Nearly 80% of breast tumors express estrogen receptor alpha (ERa) which drives tumor progression. While endocrine therapies and CDK4/6 inhibitors have increased overall survival, many patients experience recurrence of metastatic disease, often years or decades after adjuvant therapy cessation, that is largely refractory to additional lines of endocrine therapy. Metastatic disease remains incurable highlighting the need for alternative treatment approaches. Through a genome-wide CRISPR knockout screen, LMTK2 was identified as the top hit exhibiting synthetic lethality in the setting of endoxifen treatment in both endocrine-sensitive and -resistant cells. LMTK2 mRNA and protein expression was increased in all cell line and patient derived models of endocrine resistance, including estrogen deprivation (mimicking an aromatase inhibitor), tamoxifen, endoxifen, fulvestrant and abemaciclib. Copy number gain/amplification was found to exist in 67% of the 195 ERa+ human metastatic tumors analyzed with only 1% of primary tumors harboring this genomic alteration. Further, siRNA-mediated knockdown of LMTK2 enhanced the efficacy of multiple endocrine therapies, while LMTK2 overexpression was sufficient to drive endocrine resistance. LMTK2 overexpression resulted in dramatic increases in AKT and ERa phosphorylation and activity. Unlike activating PIK3CA mutations that are frequent in endocrine-resistant tumors and are known to confer resistance, LMTK2 was found to employ an alternative mechanism to activate AKT signaling by inhibiting PP1a, an AKT-inhibitory phosphatase. This proposal aims to address the central hypothesis that LMTK2 is a novel driver of endocrine resistance and ERa+ breast cancer progression. To address this hypothesis, I propose two Specific Aims. In Aim 1, I will comprehensively characterize the role of LMTK2 in mediating sensitivity of ERa+ breast cancer cell line and PDX models to endocrine therapy and CDK4/6 inhibitors. In Aim 2, I will precisely define the molecular mechanisms by which LMTK2 activates AKT and ERa signaling and determine their contribution to LMTK2- mediated endocrine resistance. Completion of this proposal will delineate a novel mechanism of endocrine resistance and potentially explain the limited efficacy that has been observed in many clinical trials utilizing PI3K/AKT inhibitors. This knowledge will lay the foundation for the establishment of LMTK2, and its downstream mediators, as informative biomarkers and novel drug targets aimed at eradicating residual cancer cells in the adjuvant setting and effectively treating resistant forms of ERa+ metastatic breast cancer, ultimately revolutionizing patient outcomes.