Epidermal Growth Factor Receptor (EGFR) is a key regulator of cell proliferation and a driver oncogene in several tumors. Many cancers have constitutively activated EGFR which leads to excessive signalling. Inhibition of EGFR using erlotinib or gefitinib significantly improves survival in patients with Non Small Cell Lung Cancer (NSCLC) while panitumumab and cetuximab are currently used in colorectal and head and neck cancer. Despite good initial responses to these drugs, the patients develop resistance and eventually die of recurrent disease. EGFR inhibitors induce stress responses that promote emergence of acquired resistance.
We identified Heat Shock protein 27 (Hsp27), a stress induced chaperone protein correlated to treatment resistance in several tumors, as a mediator of resistance to erlotinib in NSCLC. Hsp27 becomes phospho-activated after erlotinib and helps stabilize EGFR. We developed the Hsp27 antisense inhibitor OGX427 which can block the adaptive survival response and enhance the activity of erlotinib and other anti-cancer drugs and now in phase II clinical trials in lung, pancreas, bladder and prostate cancers. While the activity of OGX427 is promising, a more potent and orally active inhibitor may improve cancer control; however small molecule inhibitors are difficult to develop because of the complex structure of Hsp27.
Using a series of drug screening assays, we identified a new drug, VPC27, that functionally inhibits Hsp27 with a good tolerability profile in mice studies. The aims of this project are: a) to compare the activity of VPC27 and OGX427 on tumor proliferation/survival in different EGFR dependent solid cancers alone or in combination with EGFR inhibitors; b) to define the molecular mechanisms that link Hsp27 with resistance to EGFR inhibitors, focusing on kinases and phosphatases proteins that regulate the phosphorylation and dephosphorylation of Hsp27 and EGFR.
These studies aim to build upon two strategies that are revolutionizing the treatment landscape in cancer: the use of molecular-targeted agents inhibiting driver oncogenes and the inhibition of adaptive responses that support development of resistance. Co-targeting treatment-induced adaptive responses mediated by Hsp27 can sensitize cancer cells to EGFR inhibitors and improve the efficacy of these drugs. Moreover, understanding mechanisms by which Hsp27 regulates EGFR activity is important to identify new molecules that could be used as new targets in cancer therapy.