The RAS/RAF and PI3K/Akt pathways play a key regulatory role in cancer and are often
hit by oncogenic mutations. Despite molecular targeting, the long-term success of
monotherapy is often hampered by de novo or acquired resistance. In the case of concurrent
mutations in both pathways, horizontal combination could be a reasonable approach.
In our study, we investigated the MEK inhibitor selumetinib and PI3K/mTOR dual inhibitor
BEZ235 alone and in combination in BRAF-only mutant and BRAF + PI3K/PTEN double mutant
cancer cells using short- and long-term 2D viability assays, spheroid assays, and
immunoblots. In the 2D assays, selumetinib was more effective on BRAF-only mutant
lines when compared to BRAF + PI3K/PTEN double mutants. Furthermore, combination therapy
had an additive effect in most of the lines while synergism was observed in two of
the double mutants. Importantly, in the SW1417 BRAF + PI3K double mutant cells, synergism
was also confirmed in the spheroid and in the in vivo model. Mechanistically, p-Akt
level decreased only in the SW1417 cell line after combination treatment. In conclusion,
the presence of concurrent mutations alone did not predict a stronger response to
combination treatment. Therefore, additional investigations are warranted to identify
predictive factors that can select patients who can benefit from the horizontal combinational
inhibition of these two pathways.
