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Background: The EGFR (epidermal growth factor receptor) TKI (tyrosine kinase inhibitor) has become the standard treatment in lung cancer patients with EGFR mutations. When these patients are treated with EGFR TKI, 80~90% of the patients show responses to the drug. However the tumor begins to progress again following the development of resistance about 1 year later on average. About a half of resistance mechanisms are caused by the additional mutation of the EGFR gene (T790M), and the other half of the resistance mechanisms are caused by various mechanisms, with one of them being the overexpression of the AXL protein. Confirming AXL overexpression in circulating tumor cells (CTCs) can be an alternative method for tissue biopsy, but almost no research has been conducted on this so far. Here, we evaluate the AXL expression in CTC in case resistance occurs after the EGFR inhibitor treatment. Materials and Methods: The blood samples (10 ml) were collected from 10 EGFR TKI treated and relapsed lung cancer patients (TKI group) and 10 non-treated patients (control group). The blood samples were processed through Cytogen protocol to enrich CTCs. The enriched cells were immunofluorescent stained for CTC markers (EpCAM or Vimentin), AXL and WBC marker (CD45). The immunofluorescent stained cells were analyzed for each markers using Image Analysis program. Result: CTCs were detected by CTC markers in all patients from TKI group (range 0-210) and control group (range 1-42). AXL positive CTCs were detected in 9 out of 10 cases from TKI group and in all cases from control group. Interestingly, the quantification of AXL staining intensity in CTCs showed that AXL overexpression (3 fold or greater than baseline) was in 50% of TKI group and 20 % of control group. Conclusion: We have tested a new approach to evaluate the AXL overexpression in tumor cells of EGFR TKI resistant patients, and showed the feasibility of the this method. Most of lung cancer patients who undergo biopsy require hospitalization and some degree of complication due to biopsy is inevitable. Here we suggested that the blood-based method as a good alternative to the tissue biopsy in patients with tolerance. Citation Format: Young Hun Kim, Myoung Shin Kim, Jun Sup Lee, Hyun Kyung Lee, Jae Hyuk Lee, Young Woong Sohn, Koichi Tazaki, Kenji Nakamaru, Kenichi Wakita, Byung Hee Jeon, Seokhyung Kim, Se-Hoon Lee. Evaluation of AXL expression on circulating tumor cells from EGFR mutated lung cancer patients who have relapsed after the EGFR TKI treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1586.

Bromination of 4 by PBr 3 under Cu I catalyst produces the ambidextrous allylic halide 5 regioselectively and stereoselectively. Hetero nucleophiles distinguish the allylic carbon containing Br from the one containing Cl in 5 to give the heteroatom-substituted C 5 allylic chloride 3. The Julia olefination reaction with the C 15 sulfone 2 provides diverse retinyl ethers 1.Retinol is an essential nutrient for cell growth, proliferation, and differentiation in higher animals. This fat-soluble vitamin shows a prophylaxis effect on cancers of lung, bladder, breast, and skin. 1 The usefulness of retinol in chemoprevention is, however, limited by its excessive toxicity and inadequate tissue distribution. 2 Retinyl ethers represent a unique class of retinol analogues with more favorable therapeutic index in this regard. 3 The synthetic retinoid, retinyl methyl ether has been reported to be more active and less toxic than retinol or retinoic acid in inhibiting mammary carcinogenesis. 4 Inspired by these findings, we attempted to develop a highly efficient and general synthetic method of retinyl ethers from various alcohols, especially the biologically important ones in the expectation of obtaining new prospective properties according to the alcohols as well as an effective cancer-preventive function.The seemingly easy etherification reaction of retinol with alcohols confronts the major obstacle of the instability of retinol especially under acidic conditions, in which the activation of the hydroxyl group of retinol by acid predominantly leads to the dehydration product, anhydro vitamin A. Even under the mild and neutral condition of the Mitsunobu reaction, the coupling of retinol with phthalimide produced the desired retinylimide in a very low yield of 23%. 5 The direct etherification of retinol had a limited success only under a basic condition, where the alkoxide of retinol reacted with reactive electrophiles such as primary alkyl iodides, allylic and propargylic halides, 6 which implied that this method could not produce the retinyl ethers from aromatic alcohols including various biologically important natural products. To efficiently incorporate various alcohols with retinol, we thus devised a scheme that made use of the coupling reaction between a subunit of retinol and the functionalized ether units derived from various alcohols rather than the direct etherification reaction of retinol (Scheme 1). The Julia sulfone olefination 7 is the ideal choice of the coupling method for polyene compounds in that stable intermediates can be manipulated and that highly E-selective C=C bonds can be formed, 8 which provide a better biological activity for retinoid compounds. The C 15 sulfone compound 2 has been successfully utilized in the synthesis of carotenoids 9 as well as retinoids. 10 The success of this approach depends on the efficiency of the E-selective formation of the C 5 unit 3 from readily available isoprene.The electrophilic solvolysis reaction of conjugated dienes has been reported to produce a complicated mixture ...

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