Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY‐142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines

Abstract

Mutations in KRAS or BRAF frequently manifest in constitutive activation of the MEK1/2-ERK1/2 signalling pathway. The MEK1/2-selective inhibitor, AZD6244 (ARRY-142886), blocks ERK1/2 activation and is currently undergoing clinical evaluation. Tumour cells can vary markedly in their response to MAPK or ERK kinase (MEK) inhibitors, and the presence of a BRAF mutation is thought to predict sensitivity, with the RAS mutations being associated with intrinsic resistance. We analysed cell proliferation in a panel of 19 colorectal cancer cell lines and found no simple correlation between BRAF or KRAS mutation and sensitivity to AZD6244, though cells that harbour neither mutation tended to be resistant. Cells that were sensitive arrested in G 1 and/or underwent apoptosis and the presence of BRAF or KRAS mutation was not sufficient to predict either fate. Cell lines that were resistant to AZD6244 exhibited low or no ERK1/2 activation or exhibited coincident activation of ERK1/2 and protein kinase B (PKB), the latter indicative of activation of the PI3K pathway. In cell lines with coincident ERK1/2 and PKB activation, sensitivity to AZD6244 could be re-imposed by any of the 3 distinct PI3K/ mTOR inhibitors. We conclude that AZD6244 is effective in colorectal cancer cell lines with BRAF or KRAS mutations. Sensitivity to MEK1/2 inhibition correlates with a biochemical signature; those cells with high ERK1/2 activity (whether mutant for BRAF or KRAS) evolve a dependency upon that pathway and tend to be sensitive to AZD6244 but this can be offset by high PI3K-dependent signalling. This may have implications for the use of MEK inhibitors in combination with PI3K inhibitors. ' 2009 UICC

Assessment of the In Vivo Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer

“…4C). This finding is in accordance with previous studies and provides further evidence for the notion that KRAS mutational status alone is not sufficient as a prognostic marker for response to MEK inhibition (32)(33)(34). Moreover, given that Apc f/þ Pten f/f mice show no response to long-term MEK inhibition (Fig.…”

BRaf and MEK Inhibitors Differentially Regulate Cell Fate and Microenvironment in Human Hepatocellular Carcinoma

“…In several tumor cells, the PI3K/Akt pathway is connected to the MAPK pathway by the various Ras isoforms that are involved in the regulation of cell growth and tumorigenesis (38) and high p-Akt was associated with poor prognosis of patients with hepatocellular carcinoma (39). In addition, several studies have shown that increased p-Akt can lead to resistance to MAPK inhibition (40,41). In our study, we could also demonstrate a crosstalk between MAPK inhibition and Akt because several drugs conferred phosphorylation at Ser 473 , a central regulator of cell survival.…”

Targeting Therapeutic Liabilities Engendered by PIK3R1 Mutations for Cancer Treatment

“…Activated MAPK pathway in Ras mutant tumors mediates resistance to therapy targeting PI3K pathway [81]. Conversely, PI3K pathway has also been implicated in mediating resistance to MEK inhibitors [82,83]. Combined inhibition of PI3K and MAPK signaling may be required to achieve maximal therapeutic response.…”