Vincent Nguyen

Introduction: Lung cancer is the leading cause of cancer deaths in the world.1 Epidermal growth factor receptor (EGFR) mutations account for most of the druggable targets in lung adenocarcinoma.1 Osimertinib is a third-generation epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) that is used in the treatment of non-small lung cell carcinoma (NSCLC)1, 2. Osimertinib was developed to overcome resistance to first generation EGFR-TKIs, but it was found that cancers would eventually develop resistance to Osimertinib as well. 2,3 Overcoming these mechanisms of resistance will allow for better patient health outcomes. 2,3 The most common mutation against first generation EGFR-TKIS is T790M and the most common mutation against third generation EGFR-TKIs is C797S.4  Methods: Scientists exposed cells lines that had developed a C797S mutation against Osimertinib with first generation EGFR- TKIs.4 Scientists put the chemical structure of EGFR-TKI resistant NSCLC through a chemical library to identify which chemicals had the potential to inhibit the scaffold of the protein, then tested that chemical on resistant cell lines.5 Scientists isolated exosomes released by Osimertinib resistance NSCLC and explored the resistance changes these exosomes brought to other cells by measuring their effect on the growth of NSCLC cell lines subjected to Osimertinib.6 Osimertinib resistant NSCLC cell lines growth was measured under the effect of SHP2 inhibitors, a factor implicated in Osimertinib resistance.7 Osimertinib resistant cell lines were cultured and their proteins measured in an effort to discover mechanisms of acquired resistance. 8 Results: Osimertinib resistant cell lines with the C797S mutation could have their resistance overcome using first-generation EGFR-TKIS for a limited period before the cancer developed resistance to both. 4 The chemical CH7233163 was discovered through the chemical library and tested on a biochemical assay showing significant inhibition of Osimertinib resistant cell lines.5 Exosomes released by Osimertinib resistant cell lines were found to confer resistance to nearby cancer cells.6 IACSi-13909, a SHP2 inhibitor was found to suppress MAPK signaling and proliferation of RTK-activated tumors.7 It was found that activation of AXL receptor tyrosine kinase is a potent contributor to the development of Osimertinib resistance. 8 Tyrosine kinases have previously been linked to interactions with Rab GTPases and their interactions may contribute to Osimertinib resistance.9 Conclusion: Resistance against Osimertinib involves a multitude of different factors such as the upregulation of Rab GTPase, AXL, exosomes, and SHP2 signaling. It is possible to overcome these mechanisms by using drugs that aren’t affected by these mutations, drugs that target these resistance mechanisms, and by using drugs that completely bypass the resistant structure.

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