Strategies for chemoselective treatment of lung cancer targeting methylthioadenosine phosphorylase (MTAP) deficiency-from chemosensitivity test to translational research

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Following are our conclusion of MTAP study on resected non-small cell lung cancer without preoperative treatment.1. Diagnosis of MTAP deficiency in lung cancerNegative expression of MTAP on IHC using MTAP-MoAb and MTAP gene deletion on RT-PCR were found in 36 (44.4%) of 81 cases and in 24 (32.9%) of 73 cases. The rate concordance between two methods was 63/70 (90%) with significant correlation (p<.001). Hypermethylation in the MTAP promoter lesion was observed in all seven samples showing positive PCR and negative IHC results. IHC was specific enough to diagnose MTAP deficiency in solid tumor as lung cancer.2. Correlation of IHC between on MTAP and on P16 of P53Concordance of expression pattern on IHC was found in 71% between MTAP and p16 (MTAP(+)/p16(+) in 35 of 65 cases and MTAP(-)/p16(-) in 11 of 65) showing significant correlation (p<.001), but in only 45% between MTAP and p53 without any correlation.3. In vitro test for Selective chemotherapy by purine de novo synthesis targeting MTAP deficiency in lung cancerMTAP status did not affect the chemosensitivity of MTX nor L-ALA in the culture condition without MTA (ie. Ineffective status for salvage pathway of purine synthesis). Although ddition of MTA in culture medium had no effect on chemosensitivity of MTX nor L-ALA in MTAP (-) cancer cells, it decreased inhibition rate from 60.5% to 42.3% (p<.05) and from 55.7% to 29.9% (P<.001) in MTAP (+) cancer cells when it was tested with MTX and L-ALA, respectively.