Top Med Chem (2021) 36: 125–154
https://doi.org/10.1007/7355_2020_100
© Springer Nature Switzerland AG 2020
Published online: 14 May 2020
Exploiting Kinase Inhibitors for Cancer
Treatment: An Overview of Clinical Results
and Outlook
Athina Moschopoulou, Stefan Zwirner, Lars Zender, and Daniel Dauch
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
2 EGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
3 ALK Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
4 VEGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
5 BCR-ABL Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
6 RAF Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
7 MEK Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
8 Next Clinical Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
9 Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Abstract Mutated or dysregulated protein kinases represent major oncogenic
drivers in cancer. Due to the general druggability of these potential oncoproteins,
protein kinases have been regarded the most significant drug targets in cancer cells
for the past three decades. Starting with the approval of imatinib for targeting
BCR-ABL in leukemia positive for Philadelphia chromosome, a multitude of different kinase inhibitors have been developed and approved for the market so far.
Additionally, many new compounds with increased efficacy and target specificity
are under development and clinical testing. While several of these compounds allow
for an efficient temporary treatment success in different tumor entities, long-term
cancer control is often limited due to the development of therapy resistance. Thus,
overcoming drug resistance in tumors represents a major challenge for successful
cancer therapies in the future.
A. Moschopoulou, S. Zwirner, L. Zender (*), and D. Dauch (*)
Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Eberhard
Karls University Tuebingen, Tuebingen, Germany
German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ),
Heidelberg, Germany
e-mail: lars.zender@med.uni-tuebingen.de; daniel.dauch@med.uni-tuebingen.de
https://doi.org/10.1007/7355_2020_100
© Springer Nature Switzerland AG 2020
Published online: 14 May 2020
Exploiting Kinase Inhibitors for Cancer
Treatment: An Overview of Clinical Results
and Outlook
Athina Moschopoulou, Stefan Zwirner, Lars Zender, and Daniel Dauch
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
2 EGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
3 ALK Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
4 VEGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
5 BCR-ABL Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
6 RAF Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
7 MEK Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
8 Next Clinical Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
9 Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Abstract Mutated or dysregulated protein kinases represent major oncogenic
drivers in cancer. Due to the general druggability of these potential oncoproteins,
protein kinases have been regarded the most significant drug targets in cancer cells
for the past three decades. Starting with the approval of imatinib for targeting
BCR-ABL in leukemia positive for Philadelphia chromosome, a multitude of different kinase inhibitors have been developed and approved for the market so far.
Additionally, many new compounds with increased efficacy and target specificity
are under development and clinical testing. While several of these compounds allow
for an efficient temporary treatment success in different tumor entities, long-term
cancer control is often limited due to the development of therapy resistance. Thus,
overcoming drug resistance in tumors represents a major challenge for successful
cancer therapies in the future.
A. Moschopoulou, S. Zwirner, L. Zender (*), and D. Dauch (*)
Department of Medical Oncology and Pneumology, University Hospital Tuebingen, Eberhard
Karls University Tuebingen, Tuebingen, Germany
German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ),
Heidelberg, Germany
e-mail: lars.zender@med.uni-tuebingen.de; daniel.dauch@med.uni-tuebingen.de