Multiple resistant factors in @entity2 with primary resistance to XXXX -TK inhibitors confer poor survival.

@entity1 @entity10160 @entity470 @entity14029 @entity2 @entity156 @entity983 @entity2856 @entity669 @entity9513
OBJECTIVES: @entity470 activating mutations have been recognized as the most important predictor of response to @entity470 - @entity669 kinase inhibitors ( @entity470 -TKIs). However, 20-30% of @entity1 harboring @entity470 activating mutations show a poor response requiring investigation for underlying mechanisms. MATERIALS AND METHODS: Characteristics of 541 @entity1 with @entity2 harboring @entity470 activating mutations were analyzed to determine contributing factors that could differentiate responders and non-responders. In addition, previously suggested moleculo-pathologic factors of resistance such as IkB, @entity2856 , @entity983 , MET, @entity14029 and BIM were evaluated in @entity1 exhibiting primary resistance who had sufficient biopsied tissues available for analyses. RESULTS: Responders to @entity470 -TKIs had a higher incidence of deletion mutations and more frequent presence of @entity470 amplifications than non-responders. The median OS was 21 months (95% CI 26.1-30.4) in responders compared to 8 months (95% CI 8.7-15.8) in non-responders (p<0.001). In analyses of @entity1 with primary resistance, we found that 27.3% (6/22) of them exhibited decreased expression of IkB, and 9.1% (2/22) of @entity1 showed increased expression of @entity2856 . Loss of @entity983 was noted in 54.5%, and BIM polymorphism was found in 19% of @entity1 . No @entity1 had MET amplification, while expression of @entity14029 was detected in 5 @entity1 . Two @entity1 had simultaneous @entity9513 @entity470 or @entity10160 mutation alongside @entity470 activating mutation. Most of @entity1 exhibited @entity156 of these factors. The overall survival was worse in the group with multiple resistant factors. CONCLUSION: Our study suggests that mechanisms of primary resistance may be more complex than those underlying acquired resistance, with several factors concomitantly contributing to primary resistance.
