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Updated: Jun 22, 2026
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Tyrosine kinase inhibitors and multidrug resistance proteins: interactions and biological consequences
Amalia Azzariti1, Letizia Porcelli, Grazia M Simone
1Clinical Experimental Oncology Laboratory, National Cancer Institute, Bari, Italy. a.azzariti@oncologico.bari.it
Abstract:
Although multidrug resistance (MDR) proteins are known to play a role in drug resistance and modification pharmacodynamic characteristics of certain conventional chemotherapeutics, information about their interactions with tyrosine kinase inhibitors (TKIs) remains fragmentary and somewhat controversial. The chronic administration of TKIs in many clinical situations strongly suggests that any possible interactions with MDR transporters should be studied as a function of time. For example, short periods of exposure to TKIs could provide insights into the nature of the binding to MDR-related proteins, either as substrates or as inhibitors, whereas prolonged exposure to TKIs could provide insights into cellular responses to binding/inhibition of MDR-related proteins. In this report, we provide evidence that suggests that both Gefitinib and Vandetanib may act as transported substrates for Breast Cancer Resistance Protein (BCRP, ABCG2). Conversely, the interaction of Gefitinib and Vandetanib with P-glycoprotein (PgP, MDR1) appeared to be as inhibitors alone. Consistent with this, short periods of exposure (≤24 h) to either Gefitinib or Vandetanib increased the effectiveness of SN-38, the active metabolite of CPT-11. Conversely, prolonged exposure (5 days) decreased SN-38 effectiveness, and was associated with BCRP up-regulation and reduced cell accumulation in S-phase, possibly though reduced intracellular accumulation of SN-38. This report underlines the needs for more detailed characterisation new biologically targeted anticancer drugs, in particular analysing periods of both short and prolonged drug exposure reflecting potentially distinct situations in the clinic in order to optimise future development in combination with established chemotherapeutic approaches.
Insights
Gefitinib and Vandetanib may be substrates for Breast Cancer Resistance Protein (BCRP) and inhibitors of P-glycoprotein (PgP). Short-term exposure enhances chemotherapy, while long-term exposure reduces effectiveness and alters cellular responses.
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Multidrug resistance (MDR) proteins impact conventional chemotherapeutics, but their interaction with tyrosine kinase inhibitors (TKIs) is not fully understood.
- TKIs are chronically administered, necessitating studies on their time-dependent interactions with MDR transporters.
- Understanding these interactions is crucial for optimizing cancer treatment strategies.
Purpose of the Study:
- To investigate the time-dependent interactions of Gefitinib and Vandetanib with MDR proteins, specifically Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (PgP).
- To evaluate the impact of short-term versus prolonged TKI exposure on the effectiveness of chemotherapy agents like SN-38.
- To elucidate the cellular mechanisms underlying TKI-MDR protein interactions and their clinical implications.
Main Methods:
- In vitro assays to determine if Gefitinib and Vandetanib are substrates or inhibitors of BCRP and PgP.
- Cell-based studies exposing cancer cells to TKIs for short (≤24 h) and prolonged (5 days) periods.
- Assessment of chemotherapy agent (SN-38) effectiveness, BCRP expression, and cell cycle distribution (S-phase accumulation) under different TKI exposure conditions.
Main Results:
- Gefitinib and Vandetanib were identified as transported substrates for BCRP (ABCG2).
- Both TKIs acted as inhibitors of P-glycoprotein (PgP, MDR1).
- Short-term TKI exposure enhanced SN-38 effectiveness, while prolonged exposure decreased it, correlating with BCRP upregulation and reduced S-phase accumulation.
Conclusions:
- Gefitinib and Vandetanib exhibit distinct interactions with BCRP and PgP, acting as substrates for BCRP and inhibitors for PgP.
- Time-dependent effects of TKIs on chemotherapy efficacy highlight the importance of considering exposure duration in clinical settings.
- Further characterization of targeted anticancer drugs, considering both short and prolonged exposure scenarios, is essential for optimizing combination therapies.
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