Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Liver kinase B1 (LKB1/STK11) is a tumor suppressor frequently mutated in non-small-cell lung cancer (NSCLC).
• LKB1 mutations impair tumor suppressor activity, particularly in KRAS-mutated NSCLCs, for which effective therapies are lacking.
• Identifying novel therapeutic vulnerabilities in LKB1-mutated NSCLC is crucial.

Purpose of the Study:

• To screen FDA-approved drugs for efficacy against LKB1-deleted NSCLC.
• To investigate the therapeutic potential of Birinapant, an Inhibitor of Apoptosis Proteins (IAP) inhibitor, in LKB1-mutated NSCLC.
• To explore combination therapies for LKB1 and KRAS-mutated NSCLC.

Main Methods:

• Screening of an US FDA-approved drug library using an isogenic system of wild-type (WT) or deleted LKB1.
• Validation of Birinapant's efficacy and mechanism of action in LKB1-deleted NSCLC cells.
• Assessment of KRAS mutation impact on Birinapant response and evaluation of combination therapy with Ralimetinib (p38α inhibitor).

Main Results:

• Birinapant demonstrated significant activity specifically in LKB1-deleted NSCLC cells, inducing apoptosis via caspase activation.
• KRAS mutations were found to confer resistance to Birinapant in a panel of NSCLC cell lines.
• Combining Birinapant with Ralimetinib restored sensitivity in LKB1- and KRAS-mutated NSCLC cell lines.

Conclusions:

• Birinapant represents a potential therapeutic strategy for patients with LKB1-mutated NSCLC.
• Combination therapy with Birinapant and a KRAS pathway inhibitor like Ralimetinib may benefit patients with co-occurring LKB1 and KRAS mutations.