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Autocrine EGF and TGF-α promote primary and acquired resistance to ALK/c-Met kinase inhibitors in non-small-cell lung cancer

Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non-small-cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c-MET-specific inhibitor SGX-523 in EBC-1 cells. Next, we discovered increased autocrine production of EGF and TGF-α in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EGF and TGF-α in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-α activated EGFR signaling pathways to survive targeted c-Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC.

 

Comments:

The passage you provided describes a study investigating the role of autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) in mediating drug resistance to molecularly targeted drugs in non-small-cell lung cancer (NSCLC). Here's a breakdown of the key findings and implications of the study:

### **Background:**
- **Issue:** Drug resistance limits the effectiveness of targeted therapies in NSCLC.
- **Focus:** Investigating the role of growth factors (EGF and TGF-α) in promoting drug resistance.

### **Study Findings:**
1. **Screening Growth Factors:**
   - Identified EGF and TGF-α as growth factors causing primary resistance to ALK inhibitor TAE684 in H3122 cells and c-MET-specific inhibitor SGX-523 in EBC-1 cells.

2. **Autocrine Production in Resistant Cells:**
   - Discovered increased autocrine production of EGF and TGF-α in acquired resistant cells (H3122/TR and EBC-1/SR).
   - Overexpression of EGF and TGF-α in NSCLC cells led to resistance against TAE684 and SGX-523.

3. **Clinical Relevance:**
   - NSCLC patients with high EGF and TGF-α expression developed primary resistance to crizotinib, a targeted therapy.
 
4. **Mechanistic Insights:**
   - Autocrine EGF and TGF-α activated EGFR signaling pathways, allowing survival despite c-Met and ALK inhibition.

5. **Combination Therapy:**
   - Combined treatment with gefitinib (an EGFR inhibitor) overcame EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523.

### **Implications:**
- **Primary and Acquired Resistance:** Autocrine production of EGF and TGF-α contributes to both primary and acquired resistance against ALK and c-MET inhibitors in NSCLC.
 
- **Clinical Applications:** Understanding these mechanisms has potential implications for patient stratification and personalized treatment approaches. Patients with high EGF and TGF-α expression might benefit from combination therapies involving EGFR inhibitors alongside ALK/c-MET inhibitors.

- **Therapeutic Strategies:** Combining targeted therapies with drugs inhibiting EGFR (such as gefitinib) could enhance the effectiveness of ALK/c-MET inhibitors in patients showing high levels of EGF and TGF-α.

In summary, the study reveals a mechanism by which autocrine EGF and TGF-α contribute to drug resistance in NSCLC, suggesting a potential avenue for improving the clinical efficacy of targeted therapies in this context.

Related Products

Cat.No. Product Name Information
S1112 SGX-523 SGX-523 is a selective Met (c-Met) inhibitor with IC50 of 4 nM, no activity to BRAFV599E, c-Raf, Abl and p38α. Phase 1.

Related Targets

c-Met