Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of sunitinib in...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Gastrointestinal stromal tumors (GISTs) are often driven by mutations in c-KIT or PDGFRα.
• Imatinib is a targeted therapy, but acquired resistance is a significant clinical challenge.
• Understanding the genetic basis of resistance is crucial for optimizing GIST treatment.

Purpose of the Study:

• To investigate the association between secondary mutations in c-KIT and PDGFRα and the development of imatinib resistance in Chinese GIST patients.
• To explore the potential impact of these secondary mutations on the efficacy of sunitinib treatment following imatinib failure.

Main Methods:

• Direct sequencing was used to analyze c-KIT (exons 9, 11, 13, 14, 17, 18) and PDGFRα (exons 12, 18) mutations in 50 GIST patient samples.
• Tumor samples were collected before and after imatinib treatment to identify primary and secondary mutations.
• Patient outcomes, including imatinib resistance and response to sunitinib, were correlated with mutation status.

Main Results:

• All patients initially presented with primary c-KIT mutations (exon 11 or 9); no PDGFRα mutations were detected.
• Secondary c-KIT mutations were identified in 65.8% of imatinib-resistant tumors but in none of the imatinib-sensitive tumors (P < 0.001).
• Patients with secondary mutations showed a trend towards shorter progression-free survival on sunitinib (7 vs. 19 months), though not statistically significant (P = 0.244).

Conclusions:

• Secondary c-KIT mutations are significantly associated with acquired resistance to imatinib in Chinese GIST patients.
• The role of secondary c-KIT mutations in predicting sunitinib efficacy requires further investigation.
• Identifying secondary mutations could aid in predicting treatment response and guiding subsequent therapy choices in GIST.