5 Epilogue
As increased activity, abundance, and/or cellular distribution of wild-type and
mutant forms of RTKs is often associated with tumor establishment, growth, and
progression, small-molecule TKIs directed to clinically relevant RTKs have entered
the pharmaceutical market since the beginning of the twenty-first century,
representing innovative drugs for cancer treatment.
Their clinical use is based in the oncogene addiction phenomenon, which
describes the dependency of certain tumor cells on a specific oncogenic protein.
Even though these drugs clearly represented an impressive breakthrough in the
therapy of RTK-addicted tumors, resistance development and detection of refractory
tumors have given rise to novel therapeutic challenges, pushing the drug discovery
process forward.
The valley of death between preclinical assays and clinical practice is gradually
becoming narrower as a result of constant collaboration and exchange of information
from the bed to the bench and back, aiming to better understand the drug resistance
molecular mechanisms and to plan innovative inhibitors able to overcome the
unexpected clinical challenges.
One thing is certain, “drugs on demand” to attend to a limited group of patients is
a growing therapeutic principle in the field, and the near future will bring exciting
novelties concerning tumor resistance development, individualized therapies, selection of responsive patients, and the development of new clinical candidates.
Compliance with Ethical Standards
Funding: This study was funded by INCT-INOFAR (CNPq#465.249/2014-0; FAPERJ#E-26/
010.000090/2018)
Conflict of Interest: Authors (LML; MLCB; DNA; EJB) declare that they have no conflict of
interest.
Ethical Approval: This article does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell
141:1117–1134. https://doi.org/10.1016/j.cell.2010.06.011
2. Wagner JP, Wolf-Yadlin A, Sevecka M et al (2013) Receptor tyrosine kinases fall into distinct
classes based on their inferred signaling networks. Sci Signal 6:ra58
3. Bayraktar UD, Bayraktar S, Rocha-Lima CM (2010) Molecular basis and management of
gastrointestinal stromal tumours. World J Gastroenterol 16:2726–2734. https://doi.org/10.
3748/wjg.v16.i22.2726
192
L. M. Lima et al.
As increased activity, abundance, and/or cellular distribution of wild-type and
mutant forms of RTKs is often associated with tumor establishment, growth, and
progression, small-molecule TKIs directed to clinically relevant RTKs have entered
the pharmaceutical market since the beginning of the twenty-first century,
representing innovative drugs for cancer treatment.
Their clinical use is based in the oncogene addiction phenomenon, which
describes the dependency of certain tumor cells on a specific oncogenic protein.
Even though these drugs clearly represented an impressive breakthrough in the
therapy of RTK-addicted tumors, resistance development and detection of refractory
tumors have given rise to novel therapeutic challenges, pushing the drug discovery
process forward.
The valley of death between preclinical assays and clinical practice is gradually
becoming narrower as a result of constant collaboration and exchange of information
from the bed to the bench and back, aiming to better understand the drug resistance
molecular mechanisms and to plan innovative inhibitors able to overcome the
unexpected clinical challenges.
One thing is certain, “drugs on demand” to attend to a limited group of patients is
a growing therapeutic principle in the field, and the near future will bring exciting
novelties concerning tumor resistance development, individualized therapies, selection of responsive patients, and the development of new clinical candidates.
Compliance with Ethical Standards
Funding: This study was funded by INCT-INOFAR (CNPq#465.249/2014-0; FAPERJ#E-26/
010.000090/2018)
Conflict of Interest: Authors (LML; MLCB; DNA; EJB) declare that they have no conflict of
interest.
Ethical Approval: This article does not contain any studies with human participants or animals
performed by any of the authors.
References
1. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell
141:1117–1134. https://doi.org/10.1016/j.cell.2010.06.011
2. Wagner JP, Wolf-Yadlin A, Sevecka M et al (2013) Receptor tyrosine kinases fall into distinct
classes based on their inferred signaling networks. Sci Signal 6:ra58
3. Bayraktar UD, Bayraktar S, Rocha-Lima CM (2010) Molecular basis and management of
gastrointestinal stromal tumours. World J Gastroenterol 16:2726–2734. https://doi.org/10.
3748/wjg.v16.i22.2726
192
L. M. Lima et al.