21IRAK4 ls a Potential Target for the Treatment of Biliary Tract Cancer
Vivian Ortiz, Huaping Li, Richard Kurupi, Kian H LimAbstract
Introduction
Biliary tract cancer (BTC) is the second most common hepatic malignancy after hepatocellular carcinoma that arises from biliary epithelia with 5-year survival ranging from 2- 23%. Despite the addition of immunotherapy to the backbone treatment of gemcitabine and cisplatin, the increase in survival and progression-free survival is only modest. New therapies are needed to prolong survival in patients with this malignancy. lnterleukin-1 receptor associated kinase 4 (IRAK4) is a pivotal serine/threonine kinase in the NF-KB and MAPK pathway whose inhibition has shown sensitization to immune checkpoint inhibitors in mice with pancreatic adenocarcinoma.
Hypothesis
IRAK4 can lead to activation NF-kB in BTC in response to gemcitabine and cisplatin chemotherapy.
Methods
Human BTC cell lines were incubated with gemcitabine and cisplatin (GC). Transcriptomic analysis and protein expression were assessed by bulk RNA sequencing, Western Blot and reverse phase protein array (RPPA). Synergy analysis between gemcitabine, cisplatin and IRAK4 inhibitor CA-4948 was done using Ala mar blue and lncucyte.
Results
Incubation of GC leads to protein activation of IRAK4 and p-NF-KB and transcriptional activation of NF-kB. Preliminary RPPA analysis also show upregulation of pp38 and HSP27 in addition to p- NF-kB. Addition of CA-4948 has synergistic cytotoxic effects when incubated with GC in human BTC cell lines.
Conclusions
IRAK4 is a potential additive target for treatment of BTC. Further in vivo studies are underway to evaluate efficacy of CA-4948 effect in combination with GC and unveil its cytotoxic mechanism in BTC.