Article révisé par les pairs
Résumé : Intrinsic and acquired resistance of metastatic melanoma to V600E/KBRAF and/or MEK inhibitors, which is often caused by activation of the PI3K/AKT survival pathway, represents a major clinical challenge. Given that p53 is capable of antagonising PI3K/AKT activation we hypothesised that pharmacological restoration of p53 activity may increase the sensitivity of BRAF-mutant melanoma to MAPK-targeted therapy and eventually delay and/or prevent acquisition of drug resistance. To test this possibility we exposed a panel of vemurafenib-sensitive and resistant (innate and acquired) V600E/KBRAF melanomas to a V600E/KBRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1Met/APR-246). Strikingly, PRIMA-1Met synergised with vemurafenib to induce apoptosis and suppress proliferation of V600E/KBRAF melanoma cells in vitro and to inhibit tumour growth in vivo. Importantly, this drug combination decreased the viability of both vemurafenib-sensitive and resistant melanoma cells irrespectively of the TP53 status. Notably, p53 reactivation was invariably accompanied by PI3K/AKT pathway inhibition, the activity of which was found as a dominant resistance mechanism to BRAF inhibition in our lines. From all various combinatorial modalities tested, targeting the MAPK and PI3K signalling pathways through p53 reactivation or not, the PRIMA-1Met/vemurafenib combination was the most cytotoxic. We conclude that PRIMA-1Met through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitises V600E/KBRAF-positive melanoma to BRAF inhibitors.

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