2024 World Conference on Lung Cancer (WCLC) - Posters-P3.03I.01 Targeting RLIP76 with a Novel Small Molecule for Lung Cancer Therapy

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The study introduces a new potential therapy for non-small-cell lung cancer (NSCLC) targeting a molecule called RLIP76 with a novel small molecule inhibitor, TTU-1. Mutations in KRAS and TP53 are common in NSCLC, leading to poor prognosis and ineffective responses to conventional treatments. RLIP76, an ATP-dependent transporter, plays a significant role in cancer cell signaling and regulation by interacting with tumor suppressor p53 and other pathways, making it a novel target for cancer therapy.<br /><br />In this research, crossing RLIP76 knockout mice with p53 knockout mice demonstrated a dominant negative effect on cancer susceptibility, suggesting RLIP76 as a promising therapeutic target. The study employed virtual high throughput screening to identify TTU-1, a small molecule with strong efficacy against lung cancer cell lines. TTU-1 shows competitive binding and inhibition of RLIP76 transport activity, along with activation of caspase-3 and inhibition of DNMT and HDAC activity, which are alternative mechanisms compared to traditional chemotherapy agents like doxorubicin.<br /><br />TTU-1's anticancer effects include the modulation of gene expression in NSCLC cell lines and suppression of several cancer hallmark pathways, potentially through changes in CpG island methylation. This compound not only highlights the possibility for a first-in-class RLIP76-targeted therapy but also serves as a valuable investigative tool for further mechanistic studies. Using partial crystal structure of RLIP76 and advanced docking algorithms, TTU-1 was identified and evaluated in vitro and in vivo, showing promising results in growth inhibition of lung cancer cell lines. This positions TTU-1 as a credible candidate for future cancer-preventative and therapeutic applications, offering new insights into the treatment of NSCLC.

Asset Subtitle

Soroush Shahrokh

Meta Tag

Speaker Soroush Shahrokh

Topic Tumor Biology – Translational Biology

Keywords

NSCLC

RLIP76

TTU-1

KRAS

TP53

cancer therapy

small molecule inhibitor

caspase-3 activation

gene expression modulation

CpG island methylation