PTEN status alters the molecular route to resistance to BRAF inhibitor in melanoma

Authors

• L Huang
• Y Qin
• Q Zuo
• T Hawley
• C Seo
• H Zhang
• G Merlino
• Y Yu

Abstract

Although BRAF V600E inhibitors (BRAFi) achieved a remarkable clinical response, the strength of efficacy is short and limited by acquired drug resistance due to multiple genetic mutations. Inactivation of PTEN occurs in 30% of melanomas, frequently with a concurrent BRAF mutation. To understand the role of PTEN in resistance to BRAFi, we created the BRAFi resistant melanoma models with/without wildtype PTEN. We found that the hyperactivation of both ERK and AKT pathways was associated with BRAFi resistance in melanoma with wildtype PTEN. PTEN-impaired melanoma cells required only the ERK resistance mechanism. Moreover, we identified AXL as a key upstream effector of AKT pathway-associated resistance to BRAFi in melanoma with wildtype PTEN, but PERK, an ER stress sensor, as an essential mediator related to resistance to BRAFi in melanoma with impaired PTEN. Notably, we confirmed that blocking AXL by shRNA or small molecular inhibitors could rescue the sensitivity of resistant PTEN wildtype melanoma cells to BRAFi and inhibit their growth in vitro and in vivo. Whereas, inhibition of PERK by shRNAs or CRISPR/cas9 or small molecular inhibitors enhanced the sensitivity of resistant PTEN impaired melanoma cells to BRAFi and blocked their growth in vitro and in vivo. Our findings have uncovered the mechanism by which PTEN status contributes to acquired resistance to BRAFi, and offers a rational strategy to guide clinical testing in pre-identified subsets of patients who relapse during treatment with BRAFi. Identified protein AXL represents a promising therapeutic target for BRAF mutant melanoma patients with wildtype PTEN while PERK for BRAF mutant melanoma patients with impaired PTEN.

Scientific Focus Area: Cancer Biology

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