Prochlorperazine enhances radiosensitivity of non-small cell lung carcinoma by stabilizing GDP-bound mutant KRAS...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Lung cancer is a leading cause of cancer mortality globally.
• KRAS mutations in lung cancer confer poor prognosis and radioresistance, hindering radiotherapy effectiveness.
• Novel KRAS mutant inhibitors are needed to sensitize tumors to radiation.

Purpose of the Study:

• To identify novel radiosensitizers for KRAS-mutant lung cancer.
• To investigate the efficacy of Prochlorperazine (PCZ) as a radiosensitizer.
• To elucidate the molecular mechanisms underlying PCZ's radiosensitizing effects.

Main Methods:

• High-throughput screening of FDA-approved drugs against KRAS-mutant proteins.
• In vitro studies on KRAS-mutant and wild-type Non-Small Cell Lung Cancer (NSCLC) cells.
• Assessment of cell cycle arrest, DNA damage (γH2AX foci), and apoptosis.
• Pharmacokinetic studies and in vivo efficacy in mice xenografts.
• Analysis of the Ras/Raf/MEK/ERK signaling pathway.

Main Results:

• Prochlorperazine (PCZ) demonstrated high binding affinity to KRAS-mutant proteins, stabilizing the GDP-bound conformation.
• PCZ combined with radiation significantly decreased clonogenic survival in KRAS-mutant NSCLC cells.
• Combination treatment activated cell cycle arrest proteins (p-ATM, p53, p21) and enhanced DNA double-strand breaks (DSBs) and apoptosis.
• Pharmacokinetics revealed favorable drug accumulation in tumors.
• PCZ and radiation synergistically inhibited tumor growth in mice xenografts via Ras/Raf/MEK/ERK pathway downregulation.

Conclusions:

• Prochlorperazine (PCZ) is identified as a lead compound for radiosensitizing KRAS-mutant lung cancer.
• The combination of PCZ and radiation demonstrates significant preclinical efficacy, including tumor regression.
• PCZ holds potential as a therapeutic agent to overcome radioresistance in KRAS-mutant lung cancers.