Mutation-targeted small molecular inhibitors and immune checkpoint antibodies have extended the quality and quantity of life for patients with advanced MUTBRAF melanoma. Development of combinations based on these foundational therapies should yield further survival benefits in the near future. The combo of BRAF and MEK inhibitors specifically suppresses a form of resistance driven mainly by genetic alterations that result in MAPK- reactivation and restoration of MAPK-addiction. However, this clinically validated approach to suppress BRAF inhibitor resistance does not address epigenomic and immunologic alterations that drive resistance via MAPK- redundant and CD8 T-cell-depleted tumor states. We propose to uncover combinatorial targets in advanced V600BRAF mutant melanoma by understanding MAPK inhibitor-induced epigenomic and immune-suppressive mechanisms and their interplay. We hypothesize that MAPK inhibitor-induced tumor cell-intrinsic and extrinsic adaptations, which have been linked to innate anti-PD-1 resistance, converge on the elaboration and actions of TGF?, BMP, or VEGFA in the tumor immune microenvironment. The Lo Lab has a track record of integrating analysis of clinical and experimental resistance evolution to derive translatable preclinical strategies to suppress resistance. We propose (Aim 1) to generate a landscape perspective of epigenome-directed tumor cell-intrinsic resistance evolution by comparative analysis of human melanoma cell lines, patient-derived xenografts and immune-competent murine melanoma models. This analysis seeks to identify master transcriptional factors regulating phenotypic transitions to provide insights into resistance-regulatory growth factors and signaling pathways.
In Aim 2, we will test the hypothesis that MAPK inhibitors induce adaptive epigenomic and immune-suppressive processes via elaboration of specific TGF?s or BMPs. The action of these factors on the tumor cells and the tumor microenvironment will be analyzed, respectively, by characterization of cis-regulatory enhancer or super-enhancer modules involving TGF?/BMP receptor-regulated SMADs and by single-cell RNA-seq of dissociated tumors.
In Aim 3, we will evaluate the efficacy and mechanisms of blocking TGF?, BMP, or VEGFA on top of the MAPKi+aPD-L1 foundation and dissect the influence of the most efficacious combination on single T-cell clonotypes and epigenetic states of activation or exhaustion. Together, these studies will advance translation of our understanding of multi-faceted resistance mechanisms into next-generation combinatorial therapies for advanced melanoma.

Public Health Relevance

Therapeutic resistance is the rule rather than the exception and limits the clinical benefits of mutation-targeted and immune therapies for advanced melanoma. Translating cancer research into patient survival depends on a deep understanding of resistance mechanisms to clinically active therapies. As BRAF/MEK and PD-1 therapies were first developed in patients with advanced melanoma, rational strategies to combine these therapies carry far-reaching implications for cancer treatments in general.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Mechanisms of Cancer Therapeutics - 1 Study Section (MCT1)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Hong, Aayoung; Moriceau, Gatien; Sun, Lu et al. (2018) Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma. Cancer Discov 8:74-93
Hugo, Willy; Zaretsky, Jesse M; Sun, Lu et al. (2016) Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell 165:35-44
Titz, Bjoern; Lomova, Anastasia; Le, Allison et al. (2016) JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma. Cell Discov 2:16028
Moriceau, Gatien; Hugo, Willy; Hong, Aayoung et al. (2015) Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer Cell 27:240-56
Obenauf, Anna C; Zou, Yilong; Ji, Andrew L et al. (2015) Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 520:368-72
Hugo, Willy; Shi, Hubing; Sun, Lu et al. (2015) Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance. Cell 162:1271-85
Marusiak, Anna A; Edwards, Zoe C; Hugo, Willy et al. (2014) Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors. Nat Commun 5:3901
Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer et al. (2014) Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat Commun 5:5712
Shi, Hubing; Hugo, Willy; Kong, Xiangju et al. (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4:80-93
Shi, Hubing; Hong, Aayoung; Kong, Xiangju et al. (2014) A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov 4:69-79

Showing the most recent 10 out of 12 publications