Systematic elucidation and pharmacologic targeting on non-oncogene dependencies in imatinib-resistant...

Area of Science:

• Oncology
• Systems Biology
• Pharmacology

Background:

• Imatinib therapy is effective for gastrointestinal stromal tumors (GIST), but acquired resistance is a major clinical challenge.
• Most advanced GIST patients develop resistance to imatinib and other KIT-targeting drugs, leading to disease progression.
• Targeting non-oncogene dependencies via Master Regulators (MRs) offers a strategy to overcome resistance.

Purpose of the Study:

• To develop mutation-agnostic, network-based methodologies to identify and target MR proteins in imatinib-resistant GIST.
• To discover novel therapeutic strategies for patients with advanced GIST who have failed imatinib treatment.

Main Methods:

• Utilized unsupervised MR-based clustering of 34 GIST patient tumor samples to differentiate resistant and sensitive tumors.
• Performed high-throughput transcriptional profiling of GIST cell lines treated with FDA-approved and experimental drugs.
• Validated drug predictions in imatinib-resistant patient-derived xenograft (PDX) models.

Main Results:

• MR-based clustering successfully separated imatinib-resistant from sensitive GIST tumors.
• Six candidate drugs were identified that reversed MR activity in imatinib-resistant GIST.
• Linifanib and selinexor demonstrated significant tumor growth inhibition in PDX models, with linifanib showing marked efficacy across a wide dose range.
• In vivo MR activity reversal was confirmed for effective drugs, but not for ineffective ones.

Conclusions:

• Network-based methodologies successfully identified Master Regulators and potential therapeutic targets for imatinib-resistant GIST.
• Linifanib and selinexor represent promising drug candidates for treating advanced GIST with acquired imatinib resistance.
• The study provides a validated platform for discovering and translating MR-targeting drugs for challenging cancers.