Receptor tyrosine kinase signaling in cancer radiotherapy and its targeting for tumor radiosensitization

Abstract

Purpose: One of the most important implications of ‘Radiation Biology’ research is to improve cancer radiotherapy with minimum side effects. In this regard, combination of chemotherapy with radiation has significantly improved tumor control as well as overall survival in a variety of cancers. However, this has been achieved at the cost of significant normal tissue toxicity, due to the lack of specificity of chemotherapy. Membrane-localized receptor tyrosine kinases (RTKs) have been found to play a driving role in various hallmarks of cancer. Moreover, an early successful clinical trial using RTK-antagonist (cetuximab) to improve tumor radiosensitivity has led to an advancement in this field of research. However, a comprehensive review integrating these findings of various oncogenic RTKs, from basic radiobiology-to-radiotherapy clinical trials, is lacking in literature. Therefore, the present review analyses relevant in-vitro, in-vivo, preclinical/clinical studies and postulates the concept of ‘Radiation Biology of RTKs in Cancer’.

Conclusions: The present review elucidates the effect of IR on various oncogenic RTKs and their mechanisms, downstream signaling, intracellular translocations, their role in the repair of radiation-induced DNA damage and post-irradiation survival. Based on the knowledge derived from RTK biology and the analysis of relevant clinical trials, this review attempts to identify radiobiological considerations, which could be implemented in future trials, combining radiotherapy with RTK-antagonist. Additionally, we identify the radiosensitizing potential of recently developed RTK-targeted nanoformulations. This review would probably change the Radiation Oncologist’s view for translation of tumor-specific radiosensitization in clinic.

Keywords:

• Receptor tyrosine kinase
• EGFR
• tumor radiosensitization
• small molecule-tyrosine kinase inhibitors
• radiotherapy

Acknowledgements

AK thanks Dr K. Kian Ang and Dr. Uma Raju, Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Centre, Houston, Texas, USA for introducing me to the field of tumor radiosensitization by RTK antagonist.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Notes on contributors

Poushali Bhattacharya

Poushali Bhattacharya is currently working as a Scientific Communication Associate at Pfizer Pvt. Limited, Mumbai. She has a Master in Biotechnology and pursued her research training at Radiation Biology & Health Sciences Division, BARC. Her research interests are cancer biology, cancer immunology, tumor radiosensitization, molecular oncology and radiation signaling.

Neena G. Shetake

Neena G. Shetake is currently working as Scientific officer at Radiation Signalling and Cancer Biology Section, RB&HSD, BARC. She is pursuing her Ph.D in Life-sciences from Homi Bhabha National Institute. Her research is focused on the development of tumor-targeted nano-formulations for cancer chemo-radiotherapy and hyperthermia applications.

Badri N. Pandey

Dr Badri N. Pandey is working in RB&HSD, BARC, Mumbai since 1995. His research areas involve bystander/non-targetted effects after low/high LET radiation; role of cancer stem cells in radio-resistance; magnetic nanoparticles for targeted hyperthermia/chemo-radiotherapy and strategies for amelioration of heavy metal radio-nuclide toxicity. Dr Pandey is UICC Fellow, Switzerland.

Amit Kumar

Dr Amit Kumar is Scientific Officer in Radiation Signaling and Cancer Biology Section of Radiation Biology & Health Sciences Division, BARC, Mumbai. His research program focuses on the radiobiological effects of actinides, development of decorporation strategies, tumor radiosensitization by targeting receptor tyrosine kinases and effect of radiation on cancer cells with relevance to tumor invasion and metastasis. He has a Ph.D. in Life Sciences and postdoctoral experience in tumor radiosensitization by c-Met-RTK antagonists.