Drug Discovery Using Evolutionary Similarities in Chemical Binding to Inhibit Patient-Derived Hepatocellular...

Area of Science:

• Oncology
• Pharmacology
• Biochemistry

Background:

• Drug resistance is a major cause of therapeutic failure in refractory cancers, including hepatocellular carcinoma (HCC).
• Resistance mechanisms are complex, involving patient heterogeneity and genetic alterations in cancer cells, often exacerbated by increased drug treatment.
• Current strategies to overcome cancer drug resistance remain limited.

Purpose of the Study:

• To evaluate the clinical potential of novel sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) inhibitors, compounds 19 and 23.
• To identify molecular markers associated with anti-cancer drug resistance in HCC.
• To assess the efficacy of SERCA inhibitors in preclinical models of drug-resistant HCC.

Main Methods:

• Discovery of candidate compounds 19 and 23 using evolutionary chemical binding similarity.
• mRNA sequencing to identify molecular markers in patient-derived drug-resistant and drug-sensitive HCC.
• In vivo evaluation of compounds 19 and 23 in a tumor xenograft model using drug-resistant HCC cells.

Main Results:

• mRNA sequencing identified sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) as a dominant marker in patient-derived anti-cancer drug-resistant HCC, but not in drug-sensitive HCC.
• Candidate compounds 19 and 23 demonstrated significant tumor shrinkage in a xenograft model of drug-resistant HCC.
• SERCA inhibition emerged as a potential therapeutic target for overcoming drug resistance in HCC.

Conclusions:

• SERCA inhibitors, compounds 19 and 23, show significant potential for treating anti-cancer drug-resistant HCC.
• SERCA is a key marker and potential therapeutic target in drug-resistant HCC.
• These findings may facilitate the development of novel combinatorial strategies against highly malignant and drug-resistant cancer cells.