Acquired resistance to drugs targeting receptor tyrosine kinases

Abstract

Development of resistance to chemotherapeutic drugs represents a significant hindrance to the effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over half a century and have revealed the lack of a single cause. Rather, a multitude of mechanisms have been delineated ranging from induction and expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system and altered metabolism to name a few. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered. Chemotherapeutic agent resistance was initially assumed to be due to induction of mutations leading to a resistant phenotype. This has also been true for molecularly targeted drugs. Considerable experience has been gained from the study of agents targeting the Bcr-Abl tyrosine kinase including imatinib, dasatinib and sunitinib. It is clear that mutations alone are not responsible for the many resistance mechanisms in play. Rather, additional mechanisms are involved, ranging from epigenetic changes, alternative splicing and the induction of alternative/compensatory signaling pathways. In this review, resistance to receptor tyrosine kinase inhibitors (RTKIs), RTK-directed antibodies and antibodies that inactivate ligands for RTKs are discussed. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. The recent observation that many RTKs, including the IGF-1R, are dependence receptors that induce apoptosis in a ligand-independent manner will be discussed and the implications this signaling paradigm has on therapeutic strategies will be considered.

Figure 1. Receptor tyrosine kinase signaling pathways

Following ligand-induced receptor transphosphorylation, growth factor receptor tyrosine kinases such as the EGFR and IGF-1R recruit effector molecules containing SH2 or PTB domains to initiate a downstream cascade activating the Ras-Erk or PI3-K/Akt pathways, which impinge upon a number of additional pathways and activities including mTOR regulation.

Figure 2. Bcr-Abl signaling pathways

Formation of the Bcr-Abl fusion protein results in its mis-localization within the cell. This, in turn, leads to the phosphorylation and activation of a number of pathways common to receptor tyrosine kinases.