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Novel Combination Therapy to Overcome Adaptive and Acquired MAPK-inhibitor Resistance in Melanoma


About 50% of metastatic melanomas harbor BRAF V600 mutations, most commonly a V600E substitution, which constitutively hyper-activate the MAPK pathway and result in oncogene addiction. Therefore, the emergence of BRAF inhibitors (BRAFi) into the clinical arena have represented a true therapeutic paradigm shift for advanced melanomas. However, the almost universal occurrence of acquired resistance to BRAFi and the overabundance of initial partial responses (innate resistance) are urgent clinical problems that limit prolonged patient survival. Our recent efforts have identified 2 core resistance pathways exhibited in disease-progressive melanoma, MAPK reactivation mechanisms and PI3K–PTEN–AKT–upregulating genetic alterations. We hypothesized that these essential survival signaling pathways play a significant role in acute or adaptive resistance in BRAF-mutant melanoma. We observed that BRAF inhibition leads to early and adaptive PI3K–AKT pathway signaling, where preexisting determinants of AKT activation (e.g., PTEN mutation/expression status) limited this BRAFi-elicited PI3K–AKT signaling. However, the presence of a gain-of-function AKT mutant, for instance, would lift this restriction via BRAFi-mediated signal amplification. This study provided a mechanistic link between early, adaptive and late, acquired BRAF inhibitor resistance in melanoma, rationalizing clinical studies to target both MAPK and PI(3)K/AKT/mTOR pathways as combination therapy to delay tumor relapse. Combining BRAF/MEK targeted therapy, to combat acquired BRAFi resistance mechanisms reactivating the MAPK pathway, has been tested to be clinically superior to BRAFi monotherapy but is still challenged by acquired resistance. We show that melanomas acquire resistance to combined BRAF/MEK inhibition by augmenting or combining mechanisms observed in single-agent BRAFi resistance. Hyper-activated MAPK signaling configurations strongly favor ERK phosphorylation, leading to growth/survival finely tuned to the levels of dual inhibitors present. We show that excessive ERK rebound from MAPKi withdrawal induces cell-cycle slowdown (mediated by p38-FRA1-JUNB induction) in weakly addicted, MAPKi-resistant melanoma cells but cell death (by DNA damage and AIF cleavage) in strongly addicted cells. Insights on mechanisms of drug addiction have provided translational potential of novel combination therapy utilizing the synthetic lethality between ERK super-activation and DNA damage. Taken together, our studies have provided rationale for rapid translation of novel combination therapy to overcome relapse.

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