# Ovarian Cancer Susceptibility and Chemosensitivity to KRAS Modulation

## TL;DR

This study explores how targeting KRAS can improve chemotherapy effectiveness in ovarian cancer.

## Contribution

The paper demonstrates that multiple methods of KRAS modulation enhance chemosensitivity in ovarian cancer models.

## Key findings

- CRISPR-mediated KRAS knockdown significantly increased sensitivity to cisplatin and paclitaxel in 3D cultures.
- Pharmacological KRAS inhibition with BI2865 synergized with paclitaxel and improved efficacy in resistant cancer cells.
- KRAS modulation using PPRH oligonucleotides reduced drug IC50 values by about 50% in 2D cultures.

## Abstract

KRAS is frequently amplified or overexpressed in ovarian cancer and represents a potential therapeutic target for overcoming chemoresistance. We employed complementary approaches—CRISPR/Cas9 gene editing, Tet-ON inducible knockdown, polypurine reverse Hoogsteen hairpin (PPRH) oligonucleotides, and the pan-KRAS inhibitor BI2865—to investigate whether KRAS modulation enhances chemotherapeutic efficacy in ovarian cancer models. CRISPR-mediated KRAS knockdown in SKOV-3 cells dramatically altered three-dimensional spheroid morphology, reducing the average area six-fold, and significantly enhanced sensitivity to both cisplatin and paclitaxel in 3D cultures, where paclitaxel resistance was completely reversed. The Tet-ON system demonstrated dose-dependent chemosensitization with optimal effects at intermediate KRAS knockdown levels (~50–60%). PPRH oligonucleotides at sub-cytotoxic concentrations (50 nM) reduced cisplatin and paclitaxel IC50 values by approximately 50% in 2D cultures. Pharmacological KRAS inhibition with BI2865 produced striking synergy with paclitaxel (several hundred-fold sensitizations in 2D; complete reversal of 3D resistance), and additive effects with cisplatin. In KRAS-amplified Kuramochi cells (representing high-grade serous ovarian carcinoma), BI2865 enhanced paclitaxel efficacy, despite greater baseline chemoresistance. These findings establish KRAS as a promising chemosensitization target in ovarian cancer, with particular potential for taxane-based combination therapies.