MYC Promotes Tyrosine Kinase Inhibitor Resistance in ROS1-Fusion-Positive Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Targeted therapy for ROS1-fusion-driven non-small cell lung cancer (NSCLC) shows success.
• Therapeutic resistance remains a significant challenge in NSCLC treatment.
• MYC amplification is observed in a subset of resistant NSCLC cases.

Purpose of the Study:

• To investigate the role of MYC overexpression in driving resistance to ROS1 tyrosine kinase inhibitors (TKIs) in NSCLC.
• To explore novel combination treatment strategies to overcome ROS1-TKI resistance.

Main Methods:

• Utilized patient-derived cell lines and xenografts (LUAD-0006) with MYC amplification.
• Employed complementary approaches including pharmacologic inhibition and MYC knockdown.
• Analyzed cellular signaling pathways, including cell cycle, apoptosis, and mitochondrial function.
• Tested combinatorial treatments with mitochondrial inhibitors, CDK4/6 inhibitors, and BET bromodomain inhibitors.

Main Results:

• MYC overexpression was confirmed to induce broad resistance to ROS1 TKIs.
• Combined ROS1 inhibition and MYC knockdown were necessary to suppress proliferation in resistant cells.
• Resistant cells showed altered regulation of cell cycle, apoptosis, and mitochondrial metabolism.
• Combination therapies, including ROS1 TKI with CDK4/6 inhibitors, demonstrated synergistic effects and regained tumor control in vivo.

Conclusions:

• MYC overexpression represents a novel mechanism of ROS1-TKI resistance in NSCLC.
• Combination strategies involving ROS1 TKIs with CDK4/6 inhibitors or other targeted agents show promise for overcoming resistance.
• These findings provide a rationale for developing new therapeutic approaches for resistant NSCLC.