Dual inhibition of BCL-XL and MCL-1 is required to induce tumour regression in lung squamous cell carcinomas sensitive to FGFR inhibition

Oncogene. 2018 Aug;37(32):4475-4488. doi: 10.1038/s41388-018-0268-2. Epub 2018 May 10.

Abstract

Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells. Using patient-derived xenografts and specific inhibitors of BCL-2, BCL-XL, and MCL-1, we identified a greater reliance of lung SqCC cells on BCL-XL and MCL-1 compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitors alone provided a survival benefit in combination FGFR therapy in vivo. Only triple BCL-XL, MCL-1, and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC. Our work therefore provides a rationale for the inhibition of MCL-1, BCL-XL, and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11 / metabolism
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism
  • Cell Line, Tumor
  • Drug Therapy, Combination / methods
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Xenograft Model Antitumor Assays / methods
  • bcl-X Protein / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2L1 protein, human
  • Bcl-2-Like Protein 11
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Receptors, Fibroblast Growth Factor
  • bcl-X Protein