Parallel In Vivo Assessment of Drug Phenotypes at Various Time Points during Systemic BRAF Inhibition Reveals Tumor Adaptation and Altered Treatment Vulnerabilities

Clin Cancer Res. 2016 Dec 15;22(24):6031-6038. doi: 10.1158/1078-0432.CCR-15-2722. Epub 2016 Apr 18.

Abstract

Purpose: Treatment of BRAF-mutated melanoma tumors with BRAF inhibitor-based therapy produces high response rates, but of limited duration in the vast majority of patients. Published investigations of resistance mechanisms suggest numerous examples of tumor adaptation and signal transduction bypass mechanisms, but without insight into biomarkers that would predict which mechanism will predominate. Monitoring phenotypic response of multiple adaptive mechanisms simultaneously within the same tumor as it adapts during treatment has been elusive.

Experimental design: This study reports on a method to provide a more complete understanding of adaptive tumor responses. We simultaneously measured in vivo antitumor activity of 12 classes of inhibitors, which are suspected of enabling adaptive escape mechanisms, at various time points during systemic BRAF inhibition. We used implantable microdevices to release multiple compounds into distinct regions of a tumor to measure the efficacy of each compound independently and repeated these measurements as tumors progressed on systemic BRAF treatment.

Results: We observed varying phenotypic responses to specific inhibitors before, during, and after prolonged systemic treatment with BRAF inhibitors. Our results specifically identify PI3K, PDGFR, EGFR, and HDAC inhibitors as becoming significantly more efficacious during systemic BRAF inhibition. The sensitivity to other targeted inhibitors remained mostly unchanged, whereas local incremental sensitivity to PLX4720 declined sharply.

Conclusions: These findings suggest redundancy of several resistance mechanisms and may help identify optimal constituents of more effective combination therapy in BRAF-mutant melanoma. They also represent a new paradigm for dynamic measurement of adaptive signaling mechanisms within the same tumor during therapy. Clin Cancer Res; 22(24); 6031-8. ©2016 AACR.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Indoles / metabolism
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Mice
  • Mice, Nude
  • Mutation / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Sulfonamides / metabolism
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents
  • Indoles
  • PLX 4720
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins B-raf