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Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS)
Sreevidya Santha1,2, Xiang Ling1,2, Ieman A M Aljahdali1,3
1Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, New York, NY 14263, USA.
Abstract:
Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment.
Insights
Mutant Kras predicts bladder cancer (BC) cell sensitivity to FL118, an innovative small molecule. This study highlights mutant Kras as a biomarker for FL118 targeted therapy, improving treatment efficacy in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tumor heterogeneity in gene mutations presents a significant challenge for effective bladder cancer (BC) treatment.
- Identifying predictive biomarkers is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the efficacy of the small molecule FL118 against bladder cancer cells.
- To determine the role of Ras mutations, specifically Kras mutations, in mediating FL118's anti-cancer effects.
- To establish mutant Kras as a potential biomarker for FL118 targeted treatment.
Main Methods:
- Utilized molecular, cellular, proteomics, and animal models to assess FL118 efficacy.
- Compared FL118 activity in bladder cancer and colorectal cancer cell lines with mutant Kras versus wild-type Kras.
- Investigated FL118-induced apoptosis (PARP cleavage), inhibition of survival proteins (survivin, XIAP, Mcl-1), and reactive oxygen species (ROS) production.
- Employed gene silencing of mutant Kras to elucidate its role in FL118 response.
- Conducted in vivo studies using xenograft tumor models.
Main Results:
- FL118 demonstrated high efficacy against BC cells with Hras and Kras mutations (T24, UMUC3), but not against cells with wild-type Ras (HT1376).
- FL118 induced apoptosis and inhibited key survival proteins in mutant Kras cells, effects dependent on mutant Kras expression.
- FL118 increased ROS production in mutant Kras cells, an effect reduced by Kras silencing.
- Proteomics revealed distinct Kras-relevant signaling pathway alterations in sensitive versus resistant cells.
- In vivo studies confirmed FL118 sensitivity in UMUC3 tumors and resistance in HT1376 tumors, with Kras silencing reducing sensitivity.
Conclusions:
- Mutant Kras is essential for FL118's potent anti-cancer activity in bladder cancer.
- FL118 effectively targets bladder cancer cells harboring mutant Kras.
- Mutant Kras serves as a favorable predictive biomarker for FL118 targeted therapy, offering a promising avenue for personalized treatment strategies.
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