Acquired Resistance to Drugs Targeting Tyrosine Kinases

Abstract

Resistance to chemotherapeutic drugs exemplifies the greatest hindrance to effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over 50 years and have revealed the lack of a single cause, but instead, multiple mechanisms including induced expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system, and altered metabolism. 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. While this has occurred for molecularly targeted drugs, it is clear that drugs selectively targeting tyrosine kinases (TKs) cause the acquisition of mutational changes and resistance to inhibition. The first TK to be targeted, Bcr-Abl, led to the generation of several drugs including imatinib, dasatinib, and sunitinib that provided a rich understanding of this phenomenon. It became clear that mutations alone were not the only cause of resistance. Additional mechanisms were involved, including alternative splicing, alternative/compensatory signaling pathways, and epigenetic changes. This review will focus on resistance to tyrosine kinase inhibitors (TKIs), receptor TK (RTK)-directed antibodies, and antibodies that inactivate specific RTK ligands. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. Many RTKs, including the IGF-1R, are dependence receptors that induce ligand-independent apoptosis. How this signaling paradigm has implications on therapeutic strategies will also be considered.

Keywords: Bcr-Abl; Dependence receptors; Epidermal growth factor receptor; Receptor tyrosine kinases.

Figure 1. Receptor tyrosine kinase signaling pathway crosstalk

Following ligand-induced receptor transphosphorylation, growth factor receptor tyrosine kinases such as the ErbB1 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. Also shown is signaling by ErbB1 (EGFR).

Figure 3. Mechanism of action of ErbB2 inhibitors

A. Trastuzumab is a humanized mAb that binds to subdomain IV of ErbB2 blocking ErbB2 dimerization and ErbB2–ErbB3 complex formation which represents the major signaling unit in ErbB2 overexpressing cancer cells. This represents inhibition of ligand-independent heterodimers and signaling through PI3K and Akt. B. Pertuzumab is a humanized mAb selective for subdomain II of ErbB2 through which dimerization occurs with other ErbB family members. Pertuzumab treatment blocks ligand-induced heterodimerization and signaling. C. Lapatinib is a RTKI selective for ErbB1 and ErbB2. Lapatinib is an ATP competitive inhibitor that binds to the kinase domain of Erb1 and ErbB2 to inhibit kinase activity resulting in blockade of ligand-dependent and independent signaling (after (De Keulenaer et al., 2010)).