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 fifty 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 by 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 this signaling paradigm has implications on therapeutic strategies will also be considered.

Costunolide enhances sensitivity of K562/ADR chronic myeloid leukemia cells to doxorubicin through PI3K/Akt pathway

“…In clinical treatment, tyrosine kinase inhibitors are the most common treatment strategy for CML therapy (Kujak & Kolesar, ). However, drug resistance and clinical relapse are major limitations for CML therapy (Rosenzweig, ). The continuous activation of many downstream signaling pathways including the phosphoinositide‐3‐kinase (PI3K) pathways of Bcr/Abl participates in the regulation of cell proliferation, apoptosis, differentiation, and survival (Li et al, ).…”

PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers

“…A large number of patients treated with highly targeted agents such as dual/pan-EGFR inhibitors, to mention just a few, after an initial response to treatment rapidly experience secondary progression [35,36]. Our data revealing PIK3CA mutations as one of the main mechanisms of resistance to afatinib combined with the high percentage of USC patients known to potentially harbor such mutations in their tumors [21], may potentially explain the common resistance of these tumors to anti-HER2/neu treatment when used as single agent.…”

The systemic hallmarks of cancer

“…In general, therapeutic approaches targeting levels above the cellular level may be less affected by cancer genetic instability and heterogeneity than treatments targeting the cancer cells themselves. A suggestive example is the improvement in the long term survival associated with check-point inhibitors that target cancer tissue as opposed to cancer cells [243][244][245] as opposed to the almost universal development of acquired resistence associated to the use of tyrosine kinase inhibitors that target specific intra-cellular cancer networks [246] . An attractive top-down regulator of cancer is the nervous system and novel therapies could be designed stimulating or inhibiting some of its components [198] .…”