2024 World Conference on Lung Cancer (WCLC) - ePosters-EP.12B.04 BMF Deficiency Leads to an Increase of Drug Tolerant Persister Cells in ALK-Positive Lung Cancer

EP.12B.04 BMF Deficiency Leads to an Increase of Drug Tolerant Persister Cells in ALK-Positive Lung Cancer

Pdf Summary

The study led by T. Utsumi and colleagues investigates the role of Bcl-2 modifying factor (BMF) in the development of drug-tolerant persister (DTP) cells in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). ALK-TKI treatments are effective for these cancers but face challenges with resistance over time. DTP cells are key as they survive initial treatments and become resistant. The team used CRISPR screening to identify BMF as a critical factor impacting the survival of DTP cells during ALK-TKI treatment with drugs like alectinib and lorlatinib.<br /><br />The research found that BMF, a BH3-only protein, reduces the activity of BCL-2 proteins in response to apoptotic signals, promoting cell death. Loss of BMF led to increased survival of DTP cells post-treatment. Further experiments showed that when cells lacked BMF, the induction of apoptosis was lessened, indicating BMF's crucial role similar to that of BIM in apoptosis induction. <br /><br />The study also demonstrated that inhibiting MCL-1, a pro-survival BCL-2 protein, counteracted this resistance, suggesting a therapeutic potential. The combination of ALK-TKIs with MCL-1 inhibitors reduced the proliferation of DTP cells despite BMF depletion.<br /><br />The conclusion underscored the potential of BMF as a novel therapeutic target to improve the efficacy of ALK-TKIs by preventing DTP cell formation. Furthermore, the research highlighted MCL-1 inhibition as a possible strategy to tackle treatment resistance due to reduced BMF levels. These findings suggest new avenues for enhancing the effectiveness of targeted therapies in ALK-positive lung cancer patients.

Asset Subtitle

Takahiro Utsumi

Meta Tag

Speaker Takahiro Utsumi

Topic Metastatic Non-small Cell Lung Cancer – Targeted Therapy

Keywords

Bcl-2 modifying factor

drug-tolerant persister cells

ALK-positive NSCLC

ALK-TKI resistance

CRISPR screening

apoptosis

BIM

MCL-1 inhibition

therapeutic target

targeted therapies