Administration of these so called con ventional cytostatics usually is entailed with severe side effects. One of the main disadvantages of those substances is that they do not specifically target cancer cells but all rapidly dividing cells. This non specific mechanism of action was the rationale to develop specifically targeted anti cancer TKI. Initially, great expectations were associated with these drugs, some were met, others not. Tyrosine kinase inhibitors are a very worthy additional option for physicians in clinical management of certain types and lines of cancer treatment. However, the initial expectation of a new era of cancer therapy with substantially less side effects was not fulfilled. TKI have numerous, partly severe side ef fects eventually entailed with fatal outcome.

selelck kinase inhibitor On the other hand, when a tumor becomes resistant to conventional or targeted anti cancer therapy, TKI serve as additional options in second, third and or fourth line therapy regimes according to their approved indications. For instance Sunitinib is approved after Imatinib resist ance formation in gastrointestinal stromal tumors, and Lapatinib after non responding to antracycline or taxane based chemotherapy in combination with Trastu zumab in HER 2 positive breast cancer. Taken together, TKI are a valuable extension of the cancer drug arma mentarium. Molecular mechanism of action Many chemotherapy naive and nearly all drug resistant tumors are characterized by pronounced Receptor Tyrosine Kinase signaling.

This pattern is at least in part due to the fact that chemoresistance can be trig gered by overexpression and or activation of RTKs, ERB B1 4, IGF 1R, VEGFR 1 3, and PDGF receptor family members. The you can check here underlying mechanisms of this over activation are diverse and comprise at least the following mechanisms. → Formation of a self sustaining autocrine loop with secreted growth factors such as EGF, VEGF, PDGF, amphiregulin or others. → Expression of intrinsically active RTK in the cell membrane. → Over activation of downstream signaling by imbalance of tumor suppressor genes and oncogenes etc. In vitro investigations of cancer cell lines derived from numerous tumor entities regularly uncovered receptor tyrosine kinase activation by phosphoryl ation of specific residues located in the B subunit. Downstream the adaptor protein GAB1 recruits PI3 kinase to phosphorylated EGFR. The main function of GAB1 is to enhance PI3K AKT activation thereby prolonging MAPK signal ing. While RAS RAF MEK ERK signaling cascade usually ends up in cellular proliferation and tumorigenic transformation, enhanced AKT kinase signaling usually is entailed with evasion of apoptosis, which is the turning point in drug resistance formation.