p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib.

Intrinsic and acquired resistance of metastatic melanoma to (V600E/K)BRAF 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/K)BRAF melanomas to a (V600E/K)BRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1(Met)/APR-246). Strikingly, PRIMA-1(Met) synergised with vemurafenib to induce apoptosis and suppress proliferation of (V600E/K)BRAF 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-1(Met)/vemurafenib combination was the most cytotoxic. We conclude that PRIMA-1(Met) through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitises (V600E/K)BRAF-positive melanoma to BRAF inhibitors.

Krayem M ，Journe F ，Wiedig M ，Morandini R ，Najem A ，Salès F ，van Kempen LC ，Sibille C ，Awada A ，Marine JC ，Ghanem G ... -  《-》

Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib.

Acquaviva J ，Smith DL ，Jimenez JP ，Zhang C ，Sequeira M ，He S ，Sang J ，Bates RC ，Proia DA ... -  《-》

Mutational activation of BRAF confers sensitivity to transforming growth factor beta inhibitors in human cancer cells.

Spender LC ，Ferguson GJ ，Liu S ，Cui C ，Girotti MR ，Sibbet G ，Higgs EB ，Shuttleworth MK ，Hamilton T ，Lorigan P ，Weller M ，Vincent DF ，Sansom OJ ，Frame M ，Dijke PT ，Marais R ，Inman GJ ... -  《Oncotarget》

Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.

Ng YK ，Lee JY ，Supko KM ，Khan A ，Torres SM ，Berwick M ，Ho J ，Kirkwood JM ，Siegfried JM ，Stabile LP ... -  《-》

Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma.

Tumors, including melanomas, frequently show an accelerated glucose metabolism. Mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF), detected in about 50% of all melanomas, result in further enhancement of glycolysis. Therefore anti-metabolic substances might enhance the impact of RAF inhibitors. We have identified the two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and lumiracoxib being able to restrict energy metabolism in human melanoma cells by targeting lactate release and oxidative phosphorylation (OXPHOS). In combination with the RAF inhibitor vemurafenib strong synergism was observed: Diclofenac as well as lumiracoxib increased the anti-glycolytic impact of vemurafenib and prevented RAF-inhibitor induced metabolic reprogramming towards OXPHOS. Consequently, both NSAIDs sensitized melanoma cells to vemurafenib triggered proliferation arrest and enhanced the anti-tumor effect of RAF inhibitors from cytostatic to cytotoxic. Furthermore the addition of NSAIDs delayed the onset of RAF inhibitor resistance, most likely by counteracting the upregulation of MITF. Our data suggest that selected NSAIDs could be a promising combination partner for MAPK pathway inhibitors for the treatment of BRAFV600E mutated melanomas.

Brummer C ，Faerber S ，Bruss C ，Blank C ，Lacroix R ，Haferkamp S ，Herr W ，Kreutz M ，Renner K ... -  《-》