Context: Mutually exclusive mutations of RET, RAS or BRAF are present in 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly-differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MEK inhibitors.

Objectives: Here we investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: 4 with BRAF mutations, 4 RAS, 1 RET/PTC1, and 4 wild-type (WT).

Results: Growth of BRAF (+) cells was inhibited by the MEK antagonist PD0325901 with an IC₅₀ of < 5 nM. By contrast, RAS, RET/PTC1 or WT cells had IC₅₀ of 4 to > 1000 nM. Sensitivity was not predicted by coexisting mutations in PIK3CA or by PTEN status. Similar effects were obtained with the MEK inhibitor AZD6244. PD0325901 induced a sustained G1/S arrest in BRAF (+) but not BRAF (-) lines. PD0325901 was equipotent at inhibiting pERK1/2 after 2 h regardless of genetic background, but pERK rebounded at 24 h in most lines. MEKi-resistance was associated with partial refractoriness of pERK to further inhibition by the compounds. AZD6244 was more potent at inhibiting growth of NPA (BRAF +) than Cal62 (KRAS +) xenografts.

Conclusion: Thyroid cancers with BRAF mutation may be preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector gene mutations may have variable responses, either because they are only partially dependent on ERK, and/or because feedback responses elicit partial refractoriness to MEK inhibition.