Noah Giese

Introduction. In 11% of non-small cell lung cancers epidermal growth factor receptor (EGFR) is defective¹. An EGFR mutation allows for the receptor to constitutively turn on which results in more frequent cell proliferation¹. EGFR mutations are found more frequently in never-smokers, females, people of Asian descent². Tyrosine kinase inhibitors (TKIs) like gefitinib (Iressa) and erlotinib (Tarceva) inhibit phosphorylation of EGFR which prevent the receptor from utilizing ATP. However, cancer cells frequently develop additional mutations (T790M and C797S) which render TKI’s ineffective in approximately 50% of cases³. Through a combination therapy of a TKI with an allosteric inhibitor, AKT inhibitor, triple antibody therapy, BIM mimetic, or cMET inhibitors, treatment of EGFR mutant NSCLC becomes effective again. This abstract will discuss the potential therapies that reverse this resistance and restore TKI effectiveness. Methods. Parental PC9 cells are human adenocarcinoma from lung tissue that carry a mutated form of EGFR (delE746-A750)⁴. Mice xenografts were then prepared and allowed to grow while control and treatment combinations were given. Tumor volume was measured using a caliper. Results. The allosteric inhibitor of EGFR is named a fourth generation TKI since it does not bind to the previous mutation sites T790M or C797S. By causing an allosteric shift in confirmation, first generation TKIs are able to regain effectiveness at the active site of ATP phospholration⁵. This solution will only work however until cells develop another sequential mutation to 4^th generation treatment. Antibody therapy to EGFR (HER1), HER2, HER3 directly bind to the receptor which synergistically and persistently decreased tumor size suggesting that targeting EGFR alone may not be an optimal solution⁶. This is important to note since all other treatments exclusively target EGFR (HER1). AKT is shown to be upregulated in EGFR mutations, so an AKT inhibitor was given with a TKI and more apoptosis was observed⁷. BIM genes are concurrently deleted in 12% of EGFR mutations which prevent apoptosis. Delivering a BIM memetic in combination with a TKI resulted in decrease of tumor size⁸. Finally, a cMET inhibitor creates a heterodimer of cMET and EGFR receptors allowing TKI’s to inhibit phosphorylation⁹. Additionally, no cytotoxicity of this cMET inhibitor were found in mouse studies as well as cynomolgus monkeys.  Conclusions. Across the board, a tyrosine kinase inhibitor of EGFR is ineffective in a large number of patients with NSCLC. However, through multiple mechanisms, TKI effectiveness was restored. This further proves that combination therapy of existing treatments with novel adjutants can effectively treat non-small cell lung cancer in patients.

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