Skip to main content
SpringerLink
Log in

YAP/TEAD involvement in resistance to paclitaxel chemotherapy in lung cancer

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The Yes-associated protein (YAP) oncoprotein has been linked to both metastases and resistance to targeted therapy of lung cancer cells. We aimed to investigate the effect of YAP pharmacological inhibition, using YAP/TEA domain (TEAD) transcription factor interaction inhibitors in chemo-resistant lung cancer cells. YAP subcellular localization, as a readout for YAP activation, cell migration, and TEAD transcription factor functional transcriptional activity were investigated in cancer cell lines with up-regulated YAP, with and without YAP/TEAD interaction inhibitors. Parental (A549) and paclitaxel-resistant (A549R) cell transcriptomes were analyzed. The half-maximal inhibitory concentration (IC50) of paclitaxel or trametinib, which are Mitogen-Activated protein kinase and Erk Kinase (MEK) inhibitors, combined with a YAP/TEAD inhibitor (IV#6), was determined. A three-dimensional (3D) microfluidic culture device enabled us to study the effect of IV#6/paclitaxel combination on cancer cells isolated from fresh resected lung cancer samples. YAP activity was significantly higher in paclitaxel-resistant cell lines. The YAP/TEAD inhibitor induced a decreased YAP activity in A549, PC9, and H2052 cells, with reduced YAP nuclear staining. Wound healing assays upon YAP inhibition revealed impaired cell motility of lung cancer A549 and mesothelioma H2052 cells. Combining YAP pharmacological inhibition with trametinib in K-Ras mutated A549 cells recapitulated synthetic lethality, thereby sensitizing these cells to MEK inhibition. The YAP/TEAD inhibitor lowered the IC50 of paclitaxel in A549R cells. Differential transcriptomic analysis of parental and A549R cells revealed an increased YAP/TEAD transcriptomic signature in resistant cells, downregulated upon YAP inhibition. The YAP/TEAD inhibitor restored paclitaxel sensitivity of A549R cells cultured in a 3D microfluidic system, with lung cancer cells from a fresh tumor efficiently killed by YAP/TEAD inhibitor/paclitaxel doublet. Evidence of the YAP/TEAD transcriptional program’s role in chemotherapy resistance paves the way for YAP therapeutic targeting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

Enquiries about data availability should be directed to the authors.

References

  1. Global Cancer Observatory [Internet]. [cité 5 oct 2022]. Disponible sur: https://gco.iarc.fr/

  2. Nguyen CDK, Yi C (2019) YAP/TAZ signaling and resistance to cancer therapy. Trends Cancer 5(5):283–296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Volk-Draper L, Hall K, Griggs C, Rajput S, Kohio P, DeNardo D et al (2014) Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res 74(19):5421–5434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Han ZX, Wang HM, Jiang G, Du XP, Gao XY, Pei DS (2013) Overcoming paclitaxel resistance in lung cancer cells via dual inhibition of stathmin and Bcl-2. Cancer Biother Radiopharm 28(5):398–405

    CAS  PubMed  Google Scholar 

  5. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB (2003) Mechanisms of Taxol resistance related to microtubules. Oncogene 22(47):7280–7295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Monzó M, Rosell R, Sánchez JJ, Lee JS, O’Brate A, González-Larriba JL et al (1999) Paclitaxel resistance in non-small-cell lung cancer associated with beta-tubulin gene mutations. J Clin Oncol 17(6):1786–1793

    Article  PubMed  Google Scholar 

  7. Zhao B, Li L, Lei Q, Guan KL (2010) The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev 24(9):862–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Avruch J, Zhou D, Fitamant J, Bardeesy N, Mou F, Barrufet LR (2012) Protein kinases of the Hippo pathway: regulation and substrates. Semin Cell Dev Biol 23(7):770–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Battilana G, Zanconato F, Piccolo S (2021) Mechanisms of YAP/TAZ transcriptional control. Cell Stress 5(11):167–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang Y, Dong Q, Zhang Q, Li Z, Wang E, Qiu X (2010) Overexpression of yes-associated protein contributes to progression and poor prognosis of non-small-cell lung cancer. Cancer Sci 101(5):1279–1285

    Article  CAS  PubMed  Google Scholar 

  11. de Fraipont F, Levallet G, Creveuil C, Bergot E, Beau-Faller M, Mounawar M et al (2012) An apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial. Clin Cancer Res 18(10):2976–2986

    Article  PubMed  Google Scholar 

  12. Zanconato F, Cordenonsi M, Piccolo S (2016) YAP/TAZ at the roots of cancer. Cancer Cell 29(6):783–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tang Z, Ma Q, Wang L, Liu C, Gao H, Yang Z et al (2019) A brief review: some compounds targeting YAP against malignancies. Future Oncol 15(13):1535–1543

    Article  PubMed  Google Scholar 

  14. Sebio A, Lenz HJ (2015) Molecular pathways: hippo signaling, a critical tumor suppressor. Clin Cancer Res 21(22):5002–5007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fromond C, Espanel X, Soudé A, Chene L, Masson, P Boubia B, Montalbetti C, Broqua P. A rational approach for the discovery of inhibitors of the YAP-TEAD interaction” Proceedings of the 106th AACR Annual meeting, April 18–22, Philadelphia, Cancer Res. 2015, 75 (15 suppl.) Abst. #220

  16. Soudé A, Barth M, Luccarini JM, Delaporte S, Chirade F, Valaire C, et al. Discovery of YAP-TEAD Protein-Protein Interaction inhibitors (PPI) for treating Malignant Pleural Mesothelioma (MPM)” ACR Special Conference on The Hippo Pathway: Signaling, Cancer, and Beyond, May 8–11 San Diego 2020. Mol Cancer Res. 2020, 18 (8 _Suppl.) Abst.nr B14

  17. Dubois F, Keller M, Calvayrac O, Soncin F, Hoa L, Hergovich A et al (2016) RASSF1A suppresses the invasion and metastatic potential of human non-small cell lung cancer cells by inhibiting YAP activation through the GEF-H1/RhoB pathway. Cancer Res 76(6):1627–1640

    Article  CAS  PubMed  Google Scholar 

  18. Keller M, Dubois F, Teulier S, Martin APJ, Levallet J, Maille E et al (2019) NDR2 kinase contributes to cell invasion and cytokinesis defects induced by the inactivation of RASSF1A tumor-suppressor gene in lung cancer cells. J Exp Clin Cancer Res 38(1):158

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sontheimer-Phelps A, Hassell BA, Ingber DE (2019) Modelling cancer in microfluidic human organs-on-chips. Nat Rev Cancer 19(2):65–81

    Article  CAS  PubMed  Google Scholar 

  20. Nguyen M, De Ninno A, Mencattini A, Mermet-Meillon F, Fornabaio G, Evans SS et al (2018) Dissecting effects of anti-cancer drugs and cancer-associated fibroblasts by on-chip reconstitution of immunocompetent tumor microenvironments. Cell Rep 25(13):3884-3893.e3

    Article  CAS  PubMed  Google Scholar 

  21. Portillo-Lara R, Annabi N (2016) Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment. Lab Chip 16(21):4063–4081

    Article  CAS  PubMed  Google Scholar 

  22. Maille E, Brosseau S, Hanoux V, Creveuil C, Danel C, Bergot E et al (2019) MST1/Hippo promoter gene methylation predicts poor survival in patients with malignant pleural mesothelioma in the IFCT-GFPC-0701 MAPS Phase 3 trial. Br J Cancer 120(4):387–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Deforet M, Parrini MC, Petitjean L, Biondini M, Buguin A, Camonis J et al (2012) Automated velocity mapping of migrating cell populations (AVeMap). Nat Methods 9(11):1081–1083

    Article  CAS  PubMed  Google Scholar 

  24. Veith I, Mencattini A, Picant V, Serra M, Leclerc M, Comes MC et al (2021) Apoptosis mapping in space and time of 3D tumor ecosystems reveals transmissibility of cytotoxic cancer death. PLoS Comput Biol 17(3):e1008870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Corgnac S, Damei I, Gros G, Caidi A, Terry S, Chouaib S et al (2022) Cancer stem-like cells evade CD8+CD103+ tumor-resident memory T (TRM) lymphocytes by initiating an epithelial-to-mesenchymal transition program in a human lung tumor model. J Immunother Cancer 10(4):e004527

    Article  PubMed  PubMed Central  Google Scholar 

  26. Biondini M, Duclos G, Meyer-Schaller N, Silberzan P, Camonis J, Parrini MC (2015) RalB regulates contractility-driven cancer dissemination upon TGFβ stimulation via the RhoGEF GEF-H1. Sci Rep 5:11759

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  27. Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E et al (2015) The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 47(3):250–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M et al (2011) Role of YAP/TAZ in mechanotransduction. Nature 474(7350):179–183

    Article  CAS  PubMed  Google Scholar 

  29. Stein C, Bardet AF, Roma G, Bergling S, Clay I, Ruchti A et al (2015) YAP1 exerts its transcriptional control via TEAD-mediated activation of enhancers. PLoS Genet 11(8):e1005465

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B et al (2015) Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 17(9):1218–1227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zaidi SK, Sullivan AJ, Medina R, Ito Y, van Wijnen AJ, Stein JL, Lian JB, Stein GZ (2004) Tyrosine phosphorylation controls Runx2-mediated subnuclear targeting of YAP to repress transcription. EMBO J 23(4):790–799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fan PD, Narzisi G, Jayaprakash AD, Venturini E, Robine N, Smibert P et al (2018) YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics. Proc Natl Acad Sci 115(26):E630–E638

    Article  Google Scholar 

  33. Hsu PC, You B, Yang YL, Zhang WQ, Wang YC, Xu Z et al (2016) YAP promotes erlotinib resistance in human non-small cell lung cancer cells. Oncotarget 7(32):51922–51933

    Article  PubMed  PubMed Central  Google Scholar 

  34. Esposito D, Pant I, Shen Y, Qiao RF, Yang X, Bai Y et al (2022) ROCK1 mechano-signaling dependency of human malignancies driven by TEAD/YAP activation. Nat Commun 13(1):703

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. Stewart DJ (2010) Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol Sept 75(3):173–234

    Article  Google Scholar 

  36. Stewart DJ (2013) Wnt signaling pathway in non-small cell lung cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djt356

    Article  PubMed  Google Scholar 

  37. Wu Q, Guo J, Liu Y, Zheng Q, Li X, Wu C et al (2021) YAP drives fate conversion and chemoresistance of small cell lung cancer. Sci Adv 7(40):eabd1850

    Article  ADS  Google Scholar 

  38. Decaudin D (2011) Primary human tumor xenografted models (‘tumorgrafts’) for good management of patients with cancer. Anticancer Drugs 22(9):827–841

    Article  CAS  PubMed  Google Scholar 

  39. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE (2010) Reconstituting organ-level lung functions on a chip. Science 328(5986):1662–1668

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. Benam KH, Villenave R, Lucchesi C, Varone A, Hubeau C, Lee HH et al (2016) Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat Methods 13(2):151–157

    Article  CAS  PubMed  Google Scholar 

  41. Jain A, Barrile R, van der Meer AD, Mammoto A, Mammoto T, De Ceunynck K et al (2018) Primary human lung alveolus-on-a-chip model of intravascular thrombosis for assessment of therapeutics. Clin Pharmacol Ther 103(2):332–340

    Article  CAS  PubMed  Google Scholar 

  42. Mencattini A, Lansche C, Veith I, Erbs P, Balloul JM, Quemeneur E et al (2022) Direct imaging and automatic analysis in tumor-on-chip reveal cooperative antitumoral activity of immune cells and oncolytic vaccinia virus. Biosens Bioelectron 215:114571

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was funded by the National Agency for Research grant #ANR 2017 ‘Hippocure’ (G. Zalcman & Inventiva™ pharma company), ARC Foundation for cancer research grant #PGA RF20180206991 (MC Parrini), and ITMO INSERM grant ‘3R’, #19CR046-00 (MC Parrini & S. Descroix). We are thankful for excellent discussions and intellectual interchange to Dr. Martine Barth, PhD, (from Inventiva™) and Dr. Anne Soude, PhD (from Inventiva™).

Author information

Authors and Affiliations

  1. U830 INSERM “Cancer, Heterogenity, Instability, Plasticity”, Team “Stress and Cancer”, Institut Curie Research Centre, 26 rue d’Ulm, 75248 Cedex 05, Paris, France

    S. Brosseau, P. Abreu, C. Bouchez, L. Charon, Y. Kieffer, G. Gentric, V. Picant, I. Veith, J. Camonis, F. Mechta-Grigoriou, M. C. Parrini & G. Zalcman

  2. Medicine Faculty, Université Paris Cité, 26 rue Henri Henri Huchard, 75018, Paris, France

    S. Brosseau & G. Zalcman

  3. Thoracic Oncology Department, Clinical Investigation Centre (CIC) 1425 INSERM, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris (AP-HP), 46 rue Henri Huchard, 75018, Paris, France

    S. Brosseau & G. Zalcman

  4. PSL Research University, Paris, France

    Y. Kieffer, G. Gentric, V. Picant, I. Veith, J. Camonis, S. Descroix, F. Mechta-Grigoriou & M. C. Parrini

  5. UMR 168 CNRS “Physics and Chemistry Curie” Institut Curie Research Centre, 26 rue d’Ulm, 75248 Cedex 05, Paris, France

    S. Descroix

Authors
  1. S. Brosseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Abreu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Bouchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. Charon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y. Kieffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. Gentric
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. V. Picant
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I. Veith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Camonis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S. Descroix
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. F. Mechta-Grigoriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M. C. Parrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G. Zalcman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GZ & M-C Parrini conceived and funded the study GZ & SB wrote the first draft of the manuscript SB, PA, CB, LC, YK, VP, IV performed the experiments GG, JC, SD, F M-C, MC-P & GZ designed and supervised the experiments All authors reviewed the MS and approved the final version

Corresponding author

Correspondence to G. Zalcman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PNG 78 KB)

Figure supplementary 1: YAP-TEAD interaction inhibitors decrease cell velocity

Supplementary file2 (PNG 151 KB)

Figure supplementary 2: YAP-TEAD interaction inhibitors affect the cadherin switch during TGFbeta-induced EMT in A549 cells

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brosseau, S., Abreu, P., Bouchez, C. et al. YAP/TEAD involvement in resistance to paclitaxel chemotherapy in lung cancer. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04949-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11010-024-04949-7

Keywords

Search

Navigation