AJ-4 - Response Prediction for Anti-Receptor Tyrosine Kinase Agents

Abstract

ABSTRACT Anti-cancer agents against receptor tyrosine kinases (RTKs) have been applied clinically for the last two decades. In parallel with drug development, much effort has gone into response prediction for these agents, some of which have been successfully adopted into clinical practice. The most successful examples include HER2 amplification in breast cancer for trastuzumab or lapatinib, and epidermal growth factor receptor (EGFR) mutations and EML4/ALK rearrangement in non-small-cell lung cancer for EGFR- and ALK-tyrosine kinase inhibitors (TKIs), respectively. These examples have emphasized the necessity of genetic surveillance of target RTKs in drug and biomarker developments. Nevertheless, studies suggest that the identification of additional response-predictive markers may require a broadening of scope beyond the target RTK gene. First, the off-target issue: while many TKIs are known to have multiple kinases as their targets, only a minority of kinases is screened in the preclinical phase of drug development, and the screening is mostly done in cell-free conditions. It should be recognized that TKIs may have off-targets out of the spectrum of in vitro screening, and that cross-activity against blind targets may potentially even compromise anti-tumor activity. Secondly, the downstream alteration: multiple lines of evidence suggest that aberrant activation of downstream signaling molecules might cause resistance to anti-RTK agents. Thirdly, the peri-RTK protein association: recent studies suggest that ligand expression rather than that of the target RTK itself may be predictive for certain anti-RTK agents. In addition, several studies suggest that overexpression of certain adaptor proteins might also be predictive of response to drugs against RTKs associated with the adaptor protein.