# Exploring the role and potential of anti-viral drugs to sensitize cancer cells to chemotherapy

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $472,355

## Abstract

PROJECT SUMMARY
Chemotherapy remains the most used systemic treatment for cancers. However, despite significant
improvement in chemotherapy agents, chemoresistance remains the major problem in cancer management.
Recently, we discovered that the selective inhibitors of hepatitis C virus (HCV) NS5A replication complex
elbasvir (Elb) and daclatasvir (Dac), an analog of Elb, may be used to sensitize and re-sensitize solid and
hematologic cancer cells to chemo-drugs. We screened 1855 FDA-approved drugs and found that Elb was
among the top drugs that significantly sensitized multiple myeloma (MM) cells to carfilzomib (Cfz, proteasome
inhibitor), dexamethasone (Dex, corticosteroid), and melphalan (Mel, alkylating agent). Elb and Dac could also
re-sensitize Cfz- or Dex-resistant MM cells to Cfz or Dex respectively. In addition, we observed that Elb and
Dac enhanced chemosensitivity and re-sensitized different types of cancers such as pancreatic ductal
adenocarcinoma to 5-fluorouracil and gemcitabine (Gem), estrogen receptor‑positive breast cancer (BC) cells
to tamoxifen, and triple negative BC cells to Gem. Moreover, in the presence of Elb or Dac, lower doses of
chemo-drugs were required to induce similar cancer cell death compared to chemotherapy drugs alone. We
discovered that Elb and Dac significantly enhanced drug retention in cancer cells by inhibiting drug efflux
through ATPase phospholipid transporting 9B (ATP9B). Importantly, although tumor microenvironment (TME)
components such as tumor-associated stromal cells (TASCs) and tumor-associated macrophages (TAMs) can
protect cancer cells from chemotherapy-induced cell death, Elb and Dac abrogated TASC and TAM protective
effects by suppressing pro-tumor lipid secretion, reprogramming them to secrete type-I-IFNs for sensitizing MM
cells to Cfz, and inhibiting TAM release of deoxycytidine for overcoming Gem resistance in solid tumors.
Finally, Elb and Dac significantly improved the therapeutic efficacy of chemotherapies in MM in vivo without
increased toxicity to normal tissues. Therefore, we hypothesize that HCV NS5A inhibitors Elb and Dac can be
developed into cancer therapeutic agents due to their ability to (re)sensitize cancer cells to chemotherapies by
enhancing chemo-drug retention in tumor cells and removing TME-provided protection. To minimize the scope
of this application, we will focus on human MM (hematological malignancy) and use human MM cell lines and
primary MM cells from patients and MM PDX mouse models to test the hypothesis. Aim 1 will elucidate the role
and mechanism of Elb and Dac in sensitizing tumor cells to chemotherapy by inhibiting chemotherapeutic
drugs efflux through ATP9B and Aim 2 will elucidate the role and mechanisms of Elb and Dac in overcoming
TME-mediated extrinsic resistance by inhibiting ATP9B-mediated cholesterol uptake and deoxycytidine efflux.
Accomplishing these aims will provide the justification and tools for developing novel and effective strategies
for target...

## Key facts

- **NIH application ID:** 10948403
- **Project number:** 1R01CA285203-01A1
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Qing Yi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $472,355
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10948403

## Citation

> US National Institutes of Health, RePORTER application 10948403, Exploring the role and potential of anti-viral drugs to sensitize cancer cells to chemotherapy (1R01CA285203-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10948403. Licensed CC0.

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