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

Oncogene volume 37, pages 4475–4488 (2018)Cite this article

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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.

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Acknowledgements

We thank Leanne Scott and Hannah Johnson for excellent animal care, Stephen Wilcox for technical support and Jia-Nan Gong, David Huang, Sweta Iyer, Gemma Kelly, Najoua Lalaoui and James Whittle for advice and reagents. M-LA-L is supported by a Viertel Foundation Senior Medical Researcher Fellowship. CEW is supported by an Australian Post-graduate Award, a Cancer Therapeutics CRC top-up scholarship and a Deep Manchanda Lung Foundation Australia Early Career Fellowship. CA is supported by a Lung Foundation Australia PhD Scholarship. DM is supported by an NBCF Early Career Fellowship and NHMRC Project grant (1101378). We thank F. Colland, M. Schoumacher (Servier, France), E. Halilovic and E. Morris (Novartis, USA) for their comments and critical reading of the manuscript. This work was made possible through financial support from Servier, and grants from the Victorian Cancer Agency, the Cancer Therapeutics CRC, the Harry Secomb Foundation, the Ian Potter Foundation, the Leukaemia and Lymphoma Society, the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.

Funding

M-LA-L is supported by a Viertel Foundation Senior Medical Researcher Fellowship. CEW is supported by an Australian Post-graduate Award, a Cancer Therapeutics CRC top-up scholarship, and a Deep Manchanda Lung Foundation Australia Early Career Fellowship. CA is supported by a Lung Foundation Australia PhD Scholarship. DM is supported by an NBCF Early Career Fellowship and NHMRC Project grant (1101378). This work was made possible through financial support from Servier, grants from the Victorian Cancer Agency, the Cancer Therapeutics CRC, the Harry Secomb Foundation, the Ian Potter Foundation, the Leukemia and Lymphoma Society, the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.

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Authors and Affiliations

  1. ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    Clare E. Weeden, Casey Ah-Cann, Aliaksei Z. Holik, Julie Pasquet & Marie-Liesse Asselin-Labat

  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia

    Clare E. Weeden, Casey Ah-Cann, Aliaksei Z. Holik, Jean-Marc Garnier, Guillaume Lessene & Marie-Liesse Asselin-Labat

  3. ACRF Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    Jean-Marc Garnier & Guillaume Lessene

  4. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia

    Delphine Merino

  5. School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia

    Delphine Merino

  6. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    Delphine Merino

  7. Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC, Australia

    Guillaume Lessene

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CEW, CAC, AZH, JP, JMG, GL and MLAL are employees of the Walter and Eliza Hall Institute of Medical Research that receives research funding and milestone payments in relation to venetoclax (ABT199). The laboratory of GL and M-LA-L received research funding from Servier. The remaining authors declare no conflict of interest.

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Weeden, C.E., Ah-Cann, C., Holik, A.Z. et al. Dual inhibition of BCL-XL and MCL-1 is required to induce tumour regression in lung squamous cell carcinomas sensitive to FGFR inhibition. Oncogene 37, 4475–4488 (2018). https://doi.org/10.1038/s41388-018-0268-2

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