The clinical activity of tyrosine kinase inhibitors (TKI) varies across cancer types of cancers bearing similar receptor tyrosine kinase (RTK) mutations. Analyzing public databases, we tested the hypothesis that RTK function in normal cell could predict for TKI activity in the corresponding cancer. Classes of alterations for 16 RTK (missense mutations, amplifications, translocations) were analyzed in 17 different solid tumors, and tested as biomarkers of TKI efficacy in pivotal trials. Single agent TKI activity was minimal in cancers bearing RTK amplification. TKI activity was found correlated with the type RTK mutation but also to the functional role of the RTK in normal cell. A missense mutation of an RTK correlated with TKI efficacy when the RTK exerts an important function in the corresponding normal cell. Conversely, translocations were tissue-agnostic biomarkers, independent of RTK function in normal cells. These results provide guidance for the selection of cancers for development of novel targeted treatments.
Vanacker et al. (Wed,) studied this question.