A Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition

Abstract

BRAF inhibitor (BRAFi) therapy leads to remarkable anti-melanoma responses, but the initial tumor shrinkage is commonly incomplete, providing a nidus for subsequent disease progression. Adaptive signaling may underlie early BRAFi resistance and influence the selection pattern for genetic variants causing late, acquired resistance. We show here that BRAFi (or BRAFi+MEKi) therapy in patients frequently led to rebound p-AKT levels in their melanomas early on treatment. In cell lines, BRAFi treatment led to rebound levels of RTKs (including PDGFRβ), PIP3, pleckstrin homology domain (PHD) recruitment, and p-AKT. PTEN expression limited this BRAFi-elicited PI3K-AKT signaling, which could be rescued by introduction of a mutant AKT1 (Q79K) kown to confer acquired BRAFi resistance. Functionally, AKT1 Q79K conferred BRAFi resistance via amplifying BRAFi-elicited PI3K-AKT signaling. Additionally, MAPK pathway inhibition enhanced clonogenic growth dependency on PI3K or AKT. Thus, adaptive or genetic upregulation of AKT critically participates in melanoma survival during BRAFi therapy.

Co-clinical assessment identifies patterns of BRAF inhibitor resistance in melanoma

“…Recent whole-exome and RNA sequencing studies have identified a wide array of acquired mutations that confer resistance, including those that reactivate the MAPK pathway (NRAS, KRAS, and MEK1/2 mutations, NF1 loss, BRAF amplification, and BRAF splice variants) (7)(8)(9) and those that activate the PI3K pathway (PIK3CA, PIK3R1, and AKT1/2 mutations and PTEN loss) (10)(11)(12). Each of these provides insight into candidate second-line therapies that could potentially bypass the resistance mechanism; these include, for example, pan-RAF (13) and ERK inhibitors (14,15) or PI3K/AKT/mTOR inhibitors (16)(17)(18)(19).…”

Treatment of Vemurafenib-Resistant SKMEL-28 Melanoma Cells with Paclitaxel

“…Many previous papers showed that MAPK and PI3K/AKT pathways played key roles in this process (Johannessen et al, 2010;Paraiso et al, 2012;Shin et al, 2013). Reactivation of phosphorylation levels of ERK and AKT in acquired resistance to vemurafenib of BRAF V600E -melanoma cells were clear.…”

“…They had revealed that the decrease of expression level of tumor suppressor PTEN, HSP90 (Paraiso et al, 2012), COT (Johannessen et al, 2010) resulted in reactivation of pAKT. Many others researchers had showed that RTKs, EGFR, PDGFRβ and IGF-1R highly expressed in resistant cells and these results suggested that these molecules may play important roles in regulating of reactivation of pERK and pAKT in vemurafenib acquired resistance melanoma cells (Johannessen et al, 2010;Shin et al, 2013). Basing on these results many studies have been conducted to developing drugs with combination of inhibitors of MAKP and PI3K/AKT signaling pathways, however, up to now there is very limit effective drug has been found.…”

The next battle line against melanoma

“…[1][2][3][4] Although the resistance pathways were known, the new information on the specific activating mutations could translate to improved drug combinations tailored for individual patients.…”