Abstract A017: Targeting Tlk2 impairs breast cancer growth and engages immune responses

Abstract

Abstract The Tousled like kinases 1 and 2 (TLK1 and TLK2) are evolutionarily conserved Ser/Thr kinases that are required for genome stability and normal development in numerous organisms. Both kinases contribute to histone deposition by targeting the histone chaperones ASF1A and ASF1B and are regulated by the DNA damage response (DDR). TLK1/2 expression is ubiquitous and often elevated in human cancers with suppressed immune gene expression. In some cancer types, elevated TLK levels correlate with decreased disease-free survival. In cultured cells, TLK depletion causes replication stress, DNA damage and altered chromatin maintenance. TLK1/2 depletion increases the efficacy of DNA damage checkpoint inhibitors and PARP inhibitors and induces the Alternative-lengthening of telomeres pathway and innate immune signaling. Collectively, this data suggests that TLK activity may be a druggable anti-cancer target. To test this, we generated a conditional Tlk2 allele in mice and introduced the Mouse Mammary Tumor Virus-Polyoma Middle Tumor-antigen (MMTV-PyMT) transgene to generate breast cancers. Deletion of Tlk2 in developing breast cancer resulted in impaired primary tumor growth and a complete inhibition of lung metastasis. Characterization of the tumor microenvironment revealed elevated immune infiltration that includes activated T cells with higher levels of PD-1, which could potentially sensitize these tumors to immune checkpoint blockade. To test this possibility, we established a syngeneic breast cancer model to allow us to combine Tlk2 depletion or deletion with DDR inhibitor and anti-PD-1 therapy in vivo. Preliminary data supports the strategy of targeting Tlk2 in cancer and we will share current data from tumor models and preliminary characterization of small molecule inhibitors. Citation Format: Marina Villamor-Payá, Adrià Caballé, Jordann Smak, Mohamed-Reda Benmebarek, Camille Stephan-Otto Attolini, Travis H. Stracker. Targeting Tlk2 impairs breast cancer growth and engages immune responses [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A017.