ATP that triggers resistance to quinazoline inhibitors as well as gefitinib and
erlotinib [174–176]. To circumvent drug resistance in the clinic, structural
optimization of small molecule inhibitors is required [13]. In case of mutated
EGFR-induced resistance to gefitinib and erlotinib, newly developed EGFR inhibitors can covalently bind to the ATP-binding site of EGFR [177, 178]. That represents an example for highly selective inhibitors against mutated targets [13].
To further counter kinase inhibitor resistance, scientists break fresh ground with
innovative strategies. In the context of gatekeeper mutations, currently developed
inhibitors are going to accept varying amino acids at the gatekeeper mutation site
[179, 180]. In a second approach, kinases will be targeted at alternative binding sites
to avoid the ubiquitous ATP-binding pocket by a presumable unique cavity
[181, 182]. Apart from that, also indirect kinase targeting via inhibition of kinase
transformers would be a valid option to overcome resistance [183].
An additional clinical challenge represents the reduction or elimination of critical
toxicities associated with kinase inhibitors, such as proteinuria, skin reactions,
hypertension, or cardiotoxicity [184, 185].
Well-known examples are associated side effects of BCR-ABL inhibitors, including cytopenia, cardiotoxicity, and cardiac sequela. HER2 and ALK inhibition cause
gastric problems and dermatological irregularities. EGFR inhibition is linked to
dermatological issues, and VEGFR inhibition can trigger cardiotoxicity [186, 187].
To exclude toxicities triggered by off-target binding of the inhibitor, more
specific therapeutic strategies are required. RNA interference is not only a powerful
tool for specific gene knockdown in basic research, but it also raises expectations as a
therapeutic approach to inhibit crucial players in cancer such as kinases [13]. However, since important drug targets cannot be efficiently eradicated by RNA interference so far, clinical resistance to kinase inhibitors will continue to be an important
challenge to kinase-associated therapies [13, 188].
Altogether, the development of clinical relevant kinase inhibition has just started,
but the rapid progress in the development of molecular technologies and engineering
raises confidence for further success stories.
Compliance with Ethical Standards
Funding: L.Z. and D.D. are supported by the Deutsche Forschungsgemeinschaft (DFG, German
Research Foundation) [FOR2314 (D.D., L.Z.), SFB-TR209 (D.D., L.Z.,), SFB-TR240 (L.Z.),
Gottfried Wilhelm Leibniz Program (L.Z.)], the Deutsche Forschungsgemeinschaft (DFG, German
Research Foundation) under Germany’s excellence strategy – EXC 2180 – 390900677 [Image
Guided and Functionally Instructed Tumour Therapies (iFIT)], the Landesstiftung BadenWuerttemberg [‘Improve CRC’ (D.D., L.Z.)], the European Research Council [‘CholangioConcept’
(L.Z.)] and the German Center for Translational Cancer Research (DKTK).
Ethical Approval: This chapter does not contain any studies with human participants or animals
performed by of the authors.
Informed Consent: All authors have given their consent to this book chapter.
Conflict of Interest: The authors declare no competing financial interests.
144
A. Moschopoulou et al.
erlotinib [174–176]. To circumvent drug resistance in the clinic, structural
optimization of small molecule inhibitors is required [13]. In case of mutated
EGFR-induced resistance to gefitinib and erlotinib, newly developed EGFR inhibitors can covalently bind to the ATP-binding site of EGFR [177, 178]. That represents an example for highly selective inhibitors against mutated targets [13].
To further counter kinase inhibitor resistance, scientists break fresh ground with
innovative strategies. In the context of gatekeeper mutations, currently developed
inhibitors are going to accept varying amino acids at the gatekeeper mutation site
[179, 180]. In a second approach, kinases will be targeted at alternative binding sites
to avoid the ubiquitous ATP-binding pocket by a presumable unique cavity
[181, 182]. Apart from that, also indirect kinase targeting via inhibition of kinase
transformers would be a valid option to overcome resistance [183].
An additional clinical challenge represents the reduction or elimination of critical
toxicities associated with kinase inhibitors, such as proteinuria, skin reactions,
hypertension, or cardiotoxicity [184, 185].
Well-known examples are associated side effects of BCR-ABL inhibitors, including cytopenia, cardiotoxicity, and cardiac sequela. HER2 and ALK inhibition cause
gastric problems and dermatological irregularities. EGFR inhibition is linked to
dermatological issues, and VEGFR inhibition can trigger cardiotoxicity [186, 187].
To exclude toxicities triggered by off-target binding of the inhibitor, more
specific therapeutic strategies are required. RNA interference is not only a powerful
tool for specific gene knockdown in basic research, but it also raises expectations as a
therapeutic approach to inhibit crucial players in cancer such as kinases [13]. However, since important drug targets cannot be efficiently eradicated by RNA interference so far, clinical resistance to kinase inhibitors will continue to be an important
challenge to kinase-associated therapies [13, 188].
Altogether, the development of clinical relevant kinase inhibition has just started,
but the rapid progress in the development of molecular technologies and engineering
raises confidence for further success stories.
Compliance with Ethical Standards
Funding: L.Z. and D.D. are supported by the Deutsche Forschungsgemeinschaft (DFG, German
Research Foundation) [FOR2314 (D.D., L.Z.), SFB-TR209 (D.D., L.Z.,), SFB-TR240 (L.Z.),
Gottfried Wilhelm Leibniz Program (L.Z.)], the Deutsche Forschungsgemeinschaft (DFG, German
Research Foundation) under Germany’s excellence strategy – EXC 2180 – 390900677 [Image
Guided and Functionally Instructed Tumour Therapies (iFIT)], the Landesstiftung BadenWuerttemberg [‘Improve CRC’ (D.D., L.Z.)], the European Research Council [‘CholangioConcept’
(L.Z.)] and the German Center for Translational Cancer Research (DKTK).
Ethical Approval: This chapter does not contain any studies with human participants or animals
performed by of the authors.
Informed Consent: All authors have given their consent to this book chapter.
Conflict of Interest: The authors declare no competing financial interests.
144
A. Moschopoulou et al.