Acquired resistance to BRAF inhibition in BRAFV600E mutant gliomas

Abstract

Activating mutation of BRAF is a common finding in pediatric gliomas. As many as 14% of high grade and up to 66% of certain subtypes of low grade pediatric glioma have the BRAFV600E mutation. Small molecule inhibitors that selectively target BRAFV600E are FDA approved for melanoma and have shown significant efficacy in treating BRAFV600E glioma in pre-clinical trials. Despite showing initial anti-tumor activity, acquired drug resistance significantly limits the benefit from being treated with BRAFV600E inhibitors. Here, we have identified molecular responses to BRAFV600E inhibitor treatment in human glioma models that have substantial clinical implications. Specifically, we show that BRAFV600E inhibitor resistant cells upregulate pro-survival mediators such as Wnt, and additionally increase receptor tyrosine kinase activity, including EGFR and Axl, promoting resistance to BRAFV600E inhibition. Our results suggest strategies to circumvent acquired resistance to BRAFV600E inhibitor therapy, and thereby improve outcomes for patients with BRAFV600E gliomas.

Blockage of the mevalonate pathway overcomes the apoptotic resistance to MEK inhibitors with suppressing the activation of Akt in cancer cells

“…As the activation of Akt signaling following inhibition of the MEK pathway is known to cause apoptotic resistance to MEK inhibitors [ 7 – 17 ], we next analyzed the phosphorylation status of Akt by Western blotting after MDA-MB-231 cells were treated with CH5126766. As previously reported, the level of phosphorylated Akt was elevated when ERK was dephosphorylated by CH5126766 treatment for 24 h (Figure 2E ).…”

“…For example, the active mutation of PIK3CA gene or loss of function of PTEN gene led to the constitutive activation of PI3K-Akt signaling, which is known to confer resistance to MEK inhibition [ 4 – 6 ]. Although PIK3CA , Akt or PTEN genes are intact, MEK inhibition resulted in non-genomic Akt activation through feedback loops mediated by receptor tyrosine kinases, such as EGFR [ 7 – 10 ], FGFR [ 11 , 12 ], IGF [ 13 , 14 ], ERBB [ 12 , 15 , 16 ], MET [ 9 ] and Axl [ 17 ], which may also cause the apoptotic resistance to MEK inhibitors. Thus, the repression of activated PI3K-Akt signaling could be rational to enhance the efficacy of MEK inhibitors, and PI3K inhibitors were expected to be used with MEK inhibitors as combinatorial therapeutics.…”

Xenotransplantation of pediatric low grade gliomas confirms the enrichment of BRAF V600E mutation and preservation of CDKN2A deletion in a novel orthotopic xenograft mouse model of progressive pleomorphic xanthoastrocytoma

“…Since copy number of chromosome 9 increased despite CDKN2A deletion, addition studies (preferably in more than 1 models) are needed to examine if CDKN2A deletion is associated with the in vivo progression and in vitro growth of neurospheres, and if amplified chromosome 9 is involved in and/or drive tumor progression in PXA. Since BRAF V600E mutant gliomas often develop acquired resistance to FDA approved small molecule inhibitor [ 32 ], our PDOX model would be a powerful tool to conduct pre-clinical testing of new BRAF V600E targeting inhibitors.…”

“…Genetic analysis identified BRAF as a frequent mutation target in PLGGs, including BRAF V600E mutation [ 26 – 32 ], duplication [ 33 ] and gene fusion [ 28 – 34 ]. BRAF V600E mutation were found in WHO grade II PXA (66%), PXA with anaplasia (65%), grade I GG (18%) and grade I PA (9%) [ 29 ].…”

The Axl kinase domain in complex with a macrocyclic inhibitor offers first structural insights into an active TAM receptor kinase

“…Axl overexpression and activation are implicated in a variety of human cancers (44). Axl up-regulation confers resistance to targeted therapies in multiple cancers (19,(45)(46)(47)(48) and is also implicated in cell motility and invasion (49). Hence, Axl kinase activity remains a target to develop cancer therapeutics (50 -53).…”