Examining mechanisms of RAF inhibitor resistance in mutant BRAF melanoma
The identification of BRAF V600E as a driving mutation in approximately 50% of melanoma and the subsequent development of therapies that specifically target mutant BRAF signaling has brought new hope to many patients that suffer with this disease. However, despite initial tumor regression, almost all patients treated with RAF inhibitors develop resistance. While these RAF inhibitors are initially capable of inhibiting ERK1/2 signaling in patients that respond to treatment, the temporal kinetics of ERK1/2 activity in relation to tumor regression and tumor regrowth remain poorly defined. Several mechanisms of acquired resistance to RAF inhibitors have been identified; however, many cases of tumor progression have not been explained. Additionally, mechanisms of intrinsic resistance to RAF inhibitors have not been extensively studied. Patients that progress while on RAF inhibitor treatment are left with no effective second-line therapeutic options and ultimately succumb to the disease. Here, we found that increased expression of the stemness factor, FOXD3, in response to inhibition of ERK1/2 signaling mediates intrinsic resistance to RAF inhibitor treatment by increasing expression of ERBB3. Depletion of FOXD3 expression or direct/indirect inhibition of ERBB3 signaling sensitized cells/tumors to RAF inhibitors. Additionally, we characterized the role of Noxa downregulation in response to RAF/MEK inhibition and demonstrated that restoration of Noxa expression increased the cell death response of mutant BRAF melanoma cells to RAF/MEK targeted therapies. Finally, we used a novel, cell-based ERK1/2 reporter system to fully characterize the relationship of ERK1/2 signaling in relation to RAF inhibitor-mediated tumor regression and subsequent tumor regrowth. We identified novel molecular changes associated with tumors that acquired resistance to RAF inhibitor treatment and demonstrated that next-generation "paradox breaker" RAF inhibitors show efficacy in treating cells that have developed resistance to first-generation RAF inhibitors. These findings thoroughly explore the stages and progression of RAF inhibitor resistance, characterize new mechanisms of RAF inhibitor resistance and identify new treatment options that would benefit both treatment-naive and resistant patients.
Basile, Kevin Joseph, "Examining mechanisms of RAF inhibitor resistance in mutant BRAF melanoma" (2013). ETD Collection for Thomas Jefferson University. AAI3564349.