Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC
Aya Shiba-Ishii1, Takayuki Isagawa2, Toshihiro Shiozawa3
1Department of Diagnostic Pathology, Institute of Medicine, University of Tsukuba, Ibaraki, Japan.
Abstract:
RET fusion is an oncogenic driver in 1-2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.
Insights
Developing resistance to RET inhibitors in non-small cell lung cancer (NSCLC) involves diverse mechanisms. Targeting bypass pathways like AXL, IGF-1R, SMARCA4 loss, or mitochondria offers new therapeutic strategies for resistant RET-fusion NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- RET fusion oncogenes drive 1-2% of non-small cell lung cancer (NSCLC).
- Acquired resistance to multikinase and RET-selective inhibitors is a significant clinical challenge in RET-fusion NSCLC.
- Understanding resistance mechanisms is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate the molecular mechanisms of acquired resistance to vandetanib in CCDC6-RET fusion-driven NSCLC.
- To identify potential therapeutic vulnerabilities in resistant RET-fusion NSCLC clones.
- To explore novel treatment strategies to overcome resistance to RET inhibitors.
Main Methods:
- Establishment of vandetanib-resistant (VR) clones from LC-2/ad NSCLC cells harboring CCDC6-RET fusion.
- Whole exome sequencing (WES) and RNA sequencing (RNA-seq) to analyze VR clones.
- Functional assays to assess sensitivity to targeted inhibitors and mitochondrial inhibitors.
Main Results:
- VR clones exhibited distinct phenotypes and unique mutational/expression profiles, indicating diverse resistance mechanisms.
- Activation of bypass pathways, including AXL and IGF-1R, was observed in different VR clones.
- SMARCA4 loss was identified in a VR clone and correlated with sensitivity to dual SMARCA4/SMARCA2 inhibition.
- Increased mitochondrial damage and sensitivity to mitochondrial electron transfer chain inhibitors were noted in one VR clone.
- Increased mitochondria were also observed in post-TKI NSCLC tumor specimens.
Conclusions:
- Acquired resistance to RET inhibitors in NSCLC is driven by multiple distinct molecular mechanisms.
- Targeting bypass pathways (AXL, IGF-1R), SMARCA4/SMARCA2, or mitochondria represents promising therapeutic avenues for resistant RET-fusion NSCLC.
- Combination therapies and novel targeted approaches are essential to overcome treatment resistance in NSCLC.
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