“Lung cancer remains the leading cause of cancer-related mortality (1). This is partly due to the late stage at which lung cancer is diagnosed—more than 80% of lung cancers are diagnosed with either regional or distant metastasis (1). However, it is also partly because many patients’ tumors are ultimately refractory to therapy. The genomic revolution has empowered a detailed understanding of cancer’s genetic milieu and the identification of targetable gene alterations. In essence, these discoveries have revolutionized the management of many tumors, including lung cancer.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943221/
Stressing the need to overcome EGFR tyrosine kinase inhibitor resistance
Re: Stressing the need to overcome EGFR tyrosine kinase inhibitor resistance
Abstract
There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor–resistant clones from non–small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor–resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation. Cancer Res; 71(22); 7071–9. ©2011 AACR.
https://scholar.google.com/scholar?q=eg ... llIUusz7MJ
There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor–resistant clones from non–small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor–resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation. Cancer Res; 71(22); 7071–9. ©2011 AACR.
https://scholar.google.com/scholar?q=eg ... llIUusz7MJ
Debbie