Reversing Melanoma Cross-Resistance to BRAF and MEK Inhibitors by Co-Targeting the AKT/mTOR Pathway

Abstract

BackgroundThe sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAFV600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression. Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors. However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.Methodology/Principal FindingsThe sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically. There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS. In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.Conclusions/SignificancePrimary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation. Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs. This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor. These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.

Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis

“…Our results predict that inhibitors of the PI3K pathway may restrain the expansion of tumors with mutations in BRAF at least in part through restoration of OIS features, a concept that is receiving increasing interest (Nardella et al 2011). Furthermore, in agreement with previous data (Shao and Aplin 2010;Atefi et al 2011;Paraiso et al 2011), we show that inhibition of PI3K can enhance the cytotoxicity of targeted BRAF V600E inhibition. In particular, the observation that a PI3K inhibitor can eliminate melanoma cells that resist killing by a BRAF V600E inhibitor is of obvious interest and merits further investigation.…”

“…Although, initially, dramatic responses are seen in melanoma patients, eventually, most of them show tumor progression. Intense investigations have revealed that tumor relapse occurs owing to a variety of resistance mechanisms, some of them implicating activation of the PI3K pathway as a key player in resistance to BRAF or MEK inhibition (Shao and Aplin 2010;Atefi et al 2011;Paraiso et al 2011). Therefore, there is a dire need to find combination therapy to delay or avoid resistance.…”

Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo

“…It has recently been demonstrated that cotargeting of the MEK/ERK and PI3K/mTOR pathways with MEKi+AKTi and MEKi+mTORi 1 is effective in BRAF mutant cells with acquired resistance to BRAF inhibitors due to activating mutations in NRAS (26,27). Although these combinations also decreased cell growth in our panel of 10 human NRAS mutant melanoma cell lines, we observed that it was less effective in decreasing cell viability than MEKi+PI3K/mTORi 1,2 .…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…Beyond monotherapy, Nature Reviews | Clinical Oncology a growing body of literature supports the existence of positive mechanistic interactions of MEK inhibitor with cyclindependent kinases 4 and 6 (CDK4/6) inhibitors 73 , MDM2 antagonists 74 , or PI3K/AKT-pathway inhibitors 75 , leading to phase I and II trials investigating these combinations.…”