PAK signaling drives resistance to BRAF inhibition and dual BRAF/MEK inhibition via distinct mechanisms.
Major finding: PAK signaling drives resistance to BRAF inhibition and dual BRAF/MEK inhibition via distinct mechanisms.
Mechanism: PAK regulates JNK, β-catenin, and mTOR to promote acquired resistance to dual BRAF/MEK inhibition.
Impact: In BRAF-mutant melanoma PAK signaling may underlie acquired drug resistance to targeted therapies.
In patients with BRAF-mutant metastatic melanoma, targeted inhibition of BRAF (BRAFi) or combined inhibition of BRAF and MEK (BRAFi/MEKi) have improved outcomes, but their success is limited by the acquisition of drug resistance. Several molecular mechanisms underlying BRAFi resistance have been reported, including ERK reactivation. However, mechanisms of resistance to combined treatment with BRAFi and MEKi have not been elucidated, prompting Lu, Liu, Zhang, and colleagues to investigate combination therapy resistance mechanisms. In BRAFi-resistant cells ERK phosphorylation was increased, but in BRAFi/MEKi-resistant cells and patient-derived xenografts (PDX) ERK phosphorylation was reduced in many samples, indicating that resistance is not mediated by ERK reactivation in those cell lines. Further, in seven of eight paired pre- and post-treatment biopsies from patients treated with BRAFi/MEKi, phospho-ERK levels were reduced or remained low. In contrast, CRAF phosphorylation was increased in cells with acquired resistance. CRAF is directly phosphorylated by p21-activated kinases (PAK), and PAKs were activated in BRAFi/MEKi-resistant PDXs. PAK inhibition had no effect on parental BRAFV600E melanoma cells, but was sufficient to inhibit the growth of cells with acquired drug resistance. Both BRAFi-resistant and BRAFi/MEKi-resistant xenografts were sensitive to PAK inhibition in vivo. In BRAFi-resistant cells PAK signaling resulted in phosphorylation of CRAF and MEK to reactivate ERK. In contrast, in BRAFi/MEKi-resistant cells, PAK regulated JNK and β-catenin phosphorylation and activated mTOR signaling, bypassing ERK, and suppressed apoptosis. Collectively, these results suggest that PAK signaling drives acquired resistance to BRAFi and dual BRAFi/MEKi via distinct molecular mechanisms, and suggest the potential for therapeutic targeting of PAKs in patients with melanoma who develop resistance to BRAFi or BRAFi/MEKi.
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