Jackman D, Pao W, Riely GJ, et al
Jackman D, Pao W, Riely GJ, et al. this GNE-4997 animal xenograft model, with a stable p53-inducible tumor, provides additional evidence supporting a key role for p53 in regulating cetuximab and radiation response. Open in a separate window Fig. 6 Change in cetuximab and radiation response in cetuximab resistant tumors following induction of p53 em in vivo /em Cet-R cells with Tet-inducible p53 were inoculated into athymic mice. Following the establishment of tumors, mice were fed with either a regular diet (RD) or a regular diet containing doxycycline (Dox) to induce p53 followed by cetuximab or radiation treatment as described in Materials and Methods. The specific days and treatment intervals for Dox, cetuximab and radiation are indicated by the box and arrow GNE-4997 in each figure. The lower box shows the validation of p53 induction by western blotting in 2 representative mice receiving Dox for 8 days. Values represent GNE-4997 mean tumor size (mm3) SEM (n=10 per group). DISCUSSION The development of acquired resistance to EGFR inhibitors is emerging as a potential treatment barrier for the optimization of EGFR targeted therapy. Similar to the development of acquired resistance to other molecular targeting agents, such as imatinib (Gleevec?), acquired resistance to EGFR inhibitors also exhibits cross-resistance to other therapeutic cancer drugs and radiation (20). To explore underlying mechanisms for acquired resistance to EGFR inhibitors and radiation, we screened for differences in the expression and activity of 42 key cellular signaling proteins between EGFR inhibitor resistant cells and their corresponding parental cells. Surprisingly, we found a robust loss of p53 in all resistant clones. This consistent loss of p53 in the resistant clones to two distinct classes of EGFR targeting agents drew our attention to investigate the role of p53 in regulating acquired resistance to EGFR inhibitors and radiation. Using two different approaches to either knock down p53 in the parental cells or restore functional p53 in the resistant cells, we found that the response to cetuximab and radiation can be regulated following manipulation of p53 expression. In addition, we found that p53 may affect response to EGFR inhibitors and radiation via regulation of cell cycle arrest, apoptosis and DNA damage repair. These results suggest that p53 plays a central role in regulating acquired resistance to EGFR inhibitors and radiation. p53 is a tumor suppressor known to suppress cancer progression through the induction of cell cycle arrest, apoptosis or senescence in response to a variety of cellular stimuli. GNE-4997 Hence, loss of p53 function in cells, either through mutation or post-translational modification might therefore be expected to lead to unchecked proliferation, tumor growth and therapeutic resistance (21, 22). MAFF A substantial number of clinical and preclinical studies identify an association of p53 mutation with poor prognosis and drug resistance (17, 23) for a variety of malignancies. In breast and colorectal tumors, p53 mutations are reported to predict resistance to a host of chemotherapeutic drugs including doxorubicin, cisplatin and 5-FU (24, 25). In contrast, reports have indicated that the expression of wild-type p53 is required for the efficacy of radiation and chemotherapy. In addition to DNA damaging drugs and radiation, increasing evidence indicates the importance of p53 in regulating the response to several molecular targeted GNE-4997 agents, including EGFR inhibitors. Previous studies demonstrating that cetuximab inhibits the growth of wild-type p53, but not.