Poster abstracts
Poster number 20 submitted by Cassandra Smoak
Identification of small molecule sensitizers to ADAR1 or PACT depletion in triple-negative breast cancer
Cassandra N. Smoak (Department of Biochemistry, Purdue University), Kyle A. Cottrell (Department of Biochemistry, Purdue University)
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis that lacks targeted treatment options. The induction of viral mimicry, which is the initiation of an antiviral state due to endogenous stimuli, has emerged as a promising therapeutic strategy for the treatment of TNBC. The immune responses activated by viral mimicry drive type I interferon signaling pathways, translational inhibition, and tumor cell death. Viral mimicry can be induced by enhancing the accumulation and sensing of endogenous double-stranded RNA (dsRNA), such as by depleting the suppressors of dsRNA sensing ADAR1 and PACT. Notably, many TNBC cell lines are dependent on ADAR1 and PACT for survival, and co-depletion of ADAR1 and PACT in independent cell lines results in cell death. Given the variable dependency status of TNBC cell lines, combination approaches with PACT- or ADAR1-targeted therapeutics are necessary to effectively treat independent tumors. Considering previous work that demonstrates the ability of small molecule treatments that enhance endogenous dsRNA accumulation to sensitize cells to ADAR1 depletion, we will investigate if these drug treatments can similarly cause PACT-independent TNBC cell lines to become susceptible to depletion of PACT. Additional small molecules will also be assessed for enhancing sensitivity to ADAR1 or PACT depletion in independent cells. To accomplish this, we will perform targeted small molecule treatments and a drug-repurposing screen in ADAR1- and PACT-depleted cells. Cell viability and dsRNA sensing pathway activation will be measured to determine sensitizing drugs. Not only will the identification of drugs that render cells sensitive to ADAR1 or PACT depletion inform therapeutic strategies for ADAR1- and PACT-independent cancers, but the discovery of these small molecules may uncover the underlying factors that drive ADAR1 and PACT dependency.
Keywords: double-stranded RNA, Cancer, double-stranded RNA binding proteins