Strategies for overcoming ALK TKI resistance in ALK-fusion NSCLC

David Molkentine (Advisor: John Heymach, PhD)

      Before the emergence of targeted therapy, ALK-positive patients treated with standard chemotherapy had a median progression-free survival (PFS) in the range of 7-8 months. Over the last decade, the advent of ALK tyrosine kinase inhibitors (TKIs) produced significant improvements in the treatment of ALK-positive NSCLC, with currently over 60% of those receiving third-generation targeted therapy reaching 5-year PFS. However, for the remaining patients, on- and off-target therapeutic resistance can still limit time-on effectiveness. Therefore, to maximize efficacy, it is paramount to identify optimal next-line ALK-targeted therapies that consider any existing on-target mutations. Moreover, in cases of acquired resistance, we must devise effective combination strategies in an ALK TKI-refractory setting.

     To address these clinical needs, we evaluated on-target resistance mutations by high-throughput drug screens and generated structure/function prediction models to facilitate clinical treatment decisions. Furthermore, through genetic screening, we identified novel on-target resistance mutations to third- and fourth-generation ALK TKIs. Additionally, to elucidate the underlying mechanisms of ALK TKI off-target resistance, we investigated treatment-resistance subpopulations leveraging a multi-omics approach. From these approaches, we identified ALK TKI-generation-agnostic resistance mechanisms that rely on RTK bypass via EGFR/HER3 signaling, and that targeting these drivers could favorably re-sensitize ALK TKI-resistant tumors.  

      When taken together, these data provide a mutation-specific drug-efficacy roadmap for multiple generations of ALK inhibitors, which can guide optimal treatment strategies in the next-line clinical setting. Moreover, we elucidated compensatory upregulation of EGFR/HER3, and we demonstrate that targeting these drivers in an ALK TKI-treatment-refractory setting can be an effective strategy for overcoming resistant disease.

Advisory Committee:

• John Heymach, PhD, Chair
• Kyle Concannon, MD
• Don Gibbons, MD, PhD
• Ralf Kittler, PhD 
• Marcelo Vailati Negrao, MD 
• Alexandre Reuben, PhD

Join via Zoom (Please contact Mr. Molkentine for his Zoom meeting info.)