EFFECT OF A PENICILLIN DERIVATIVE ON THE EXPRESSION LEVELS OF β- CATENIN IN MELANOMA CELLS WITH DIFFERENT SENSITIVITY TO BRAF INHIBITORS

SOFIA BAJICOFF; ELIZABETH BARRIONUEVO; PATRICIA G. CORNIER; CARINA M. DELPICCOLO; ERNESTO G. MATA; VIVIANA BLANK; LEONOR P. ROGUIN

Congreso; Reunión Anual de Sociedades de Biociencias; 2022

We have previously demonstrated that TAP7f, a synthetic derivative formed bypenicillin linked to the dipeptide Leu-Phe through a triazole group, inhibited melanomametastasis by downregulating β-catenin. Since it has been reported that melanomacells resistant to BRAF inhibitors (BRAFi) express higher levels of β-catenin, blockingWnt/ β-catenin signaling could be considered a useful strategy to improve cellresponse. In this study we examined the mechanism of action of TAP7f in melanomacells sensitive (A375, BRAF V600E ) and resistant (SB2, NRAS Q61K ) to BRAFi. The cytotoxicpotency of TAP7f on these cell lines was first determined, being IC 50 values of 10.0 ± 1µM and 9.0 ± 3 µM for A375 and SB2 cells, respectively (72 h, n=3). In addition, IC 50values of 7.7 ± 0.5 nM and 2.1 ± 0.9 nM were obtained for dabrafenib (D, BRAFi) andTrametinib (T, MEKi) in A375 cells, whereas SB2 cells were more resistant to theseinhibitors (IC 50 D: > 30 µM; IC 50 T: > 20 nM). Western Blot assays revealed that TAP7f(20 µM) reduced 67.5 ± 0.6 % and 59.1 ± 0.1 % the expression levels of β-catenin inA375 and SB2 cells, respectively, after 24 h of incubation. Under similar experimentalconditions, TAP7f increased the phosphorylation of Ser 33/37 of β-catenin in both celllines, a target region for β-catenin degradation. Furthermore, when A375 and SB2melanoma cells were incubated with TAP7f in the presence of MG132, a proteasomeinhibitor, a significant reversion of TAP7f inhibitory effect on β-catenin levels wasobserved. In summary, our results suggest that TAP7f downregulates β-catenin levelsby promoting its degradation via proteasome in melanoma cell lines with differentgenetic profile, regardless of sensitivity to BRFA inhibitors. This behavior positions thispenicillin derivative as a promising agent for the treatment of BRAFi-resistant cells.