Resistance to HER2-Targeted Therapies Results in Upregulation of MCL-1 and Sensitivity to Olaparib

Resistance to HER2-Targeted Therapies Results in Upregulation of MCL-1 and Sensitivity to Olaparib

Loading document ...
Page
of
Loading page ...

Author(s)

Author(s): Andrew Armstrong, Mathew Najor, Trevor Rempert, Faraz Bishehsari, Abde M. Abukhdeir, Melody A. Cobleigh

Download Full PDF Read Complete Article

DOI: 10.18483/ijSci.2407 16 33 7-17 Volume 9 - Dec 2020

Abstract

HER2 amplification results in increased tumor growth and aggressiveness in breast cancer. Despite advancements in HER2-targeted therapy, treatment resistance, cancer recurrence, and metastasis remain significant obstacles in combating this deadly disease. PARP inhibitors, have emerged as a promising class of drugs targeting cancers deficient in homologous recombination repair. Recent preclinical evidence suggests that PARP inhibitors exhibit sensitivity in cancers with high replication stress and genomic instability, as well as some HER2 positive breast cancer cell lines. To investigate the relationship between HER2 amplification and PARP inhibitor sensitivity, we utilized isogenic models of HER2-positive breast cancer, whereby cells were either sensitive or resistant to lapatinib and treated with the PARP inhibitor olaparib used as a single agent, or in combination with HER2-targeted therapies. Our results show that HER2 overexpressing MCF-10A cells are highly sensitivity to single-agent olaparib. The addition of trastuzumab and lapatinib resulted in a synergistic increase in toxicity. To determine if olaparib could be used to overcome resistance to lapatinib, we obtained SKBR3 cells conditioned to be resistant to lapatinib. Despite resistance to lapatinib, these cells continue to exhibit sensitivity to olaparib. Reverse phase protein analysis revealed that lapatinib resistant clones exhibited a statistically-significant increase in protein expression of the apoptosis inhibitor MCL-1, which is decreased upon olaparib treatment resulting in apoptosis. Taken together, our findings suggest that HER2 overexpression may predict sensitivity to olaparib alone, or in combination with trastuzumab and lapatinib. Lapatinib resistant HER2-positive breast cancer cells are sensitive to olaparib, possibly through downregulation of MCL-1.

References

  1. Arteaga, C.L., et al., Treatment of HER2-positive breast cancer: current status and future perspectives. Nat Rev Clin Oncol, 2011. 9(1): p. 16-32.
  2. Karunagaran, D., et al., ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J, 1996. 15(2): p. 254-64.
  3. Vernieri, C., et al., Resistance mechanisms to anti-HER2 therapies in HER2-positive breast cancer: Current knowledge, new research directions and therapeutic perspectives. Crit Rev Oncol Hematol, 2019. 139: p. 53-66.
  4. Mohd Sharial, M.S., J. Crown, and B.T. Hennessy, Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer. Ann Oncol, 2012. 23(12): p. 3007-16.
  5. Ray Chaudhuri, A. and A. Nussenzweig, The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol, 2017. 18(10): p. 610-621.
  6. Yi, M., et al., Advances and perspectives of PARP inhibitors. Exp Hematol Oncol, 2019. 8: p. 29.
  7. Shen, Y., M. Aoyagi-Scharber, and B. Wang, Trapping Poly(ADP-Ribose) Polymerase. J Pharmacol Exp Ther, 2015. 353(3): p. 446-57.
  8. Ellsworth, R.E., et al., Amplification of HER2 is a marker for global genomic instability. BMC Cancer, 2008. 8: p. 297.
  9. Nowsheen, S., et al., HER2 overexpression renders human breast cancers sensitive to PARP inhibition independently of any defect in homologous recombination DNA repair. Cancer Res, 2012. 72(18): p. 4796-806.
  10. Garcia-Parra, J., et al., Poly (ADP-ribose) polymerase inhibition enhances trastuzumab antitumour activity in HER2 overexpressing breast cancer. Eur J Cancer, 2014. 50(15): p. 2725-34.
  11. Shimo, T., et al., Antitumor and anticancer stem cell activity of a poly ADP-ribose polymerase inhibitor olaparib in breast cancer cells. Breast Cancer, 2014. 21(1): p. 75-85.
  12. Tang, Y., et al., Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors. Mol Pharmacol, 2012. 82(2): p. 322-32.
  13. Pierce, A., et al., Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non-triple-negative breast cancer cell lines. Cancer Biol Ther, 2013. 14(6): p. 537-45.
  14. MedSIR, Olaparib+Trastuzumab in HER2 + ,Breast Cancer Susceptibility Gene (BRCA) Mutated or Homologous Recombination Deficient (HRD) Advanced Breast Cancer. 2019, https://ClinicalTrials.gov/show/NCT03931551.
  15. Turturro, S.B., et al., Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway. Breast Cancer Res Treat, 2019. 177(2): p. 325-333.
  16. Soetaert, K., plot3D: Plotting Multi-Dimensional Data. 2017.
  17. Team, R.C., R: A Language and Environment for Statistical Computing. 2018, R Foundation for Statistical Computing.
  18. Ianevski, A., et al., SynergyFinder: a web application for analyzing drug combination dose-response matrix data. Bioinformatics, 2017. 33(15): p. 2413-2415.
  19. Hu, J., et al., Non-parametric quantification of protein lysate arrays. Bioinformatics, 2007. 23(15): p. 1986-94.
  20. Ju, Z., et al., Development of a robust classifier for quality control of reverse-phase protein arrays. Bioinformatics, 2015. 31(6): p. 912-8.
  21. Ritchie, M.E., et al., limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res, 2015. 43(7): p. e47.
  22. DiScala, M., et al., Loss of STAT6 leads to anchorage-independent growth and trastuzumab resistance in HER2+ breast cancer cells. PLoS One, 2020. 15(6): p. e0234146.
  23. Gustin, J.P., et al., Knockin of mutant PIK3CA activates multiple oncogenic pathways. Proc Natl Acad Sci U S A, 2009. 106(8): p. 2835-40.
  24. Yadav, B., et al., Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model. Comput Struct Biotechnol J, 2015. 13: p. 504-13.
  25. C.I., B., The toxicity of poisons applied jointly. Annals of Applied Biology, 1939. 26: p. 585-615.
  26. Berenbaum, M.C., What is synergy? Pharmacol Rev, 1989. 41(2): p. 93-141.
  27. Pilie, P.G., et al., PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers. Clin Cancer Res, 2019. 25(13): p. 3759-3771.
  28. Stanley, J., et al., PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers. Breast Cancer Res Treat, 2015. 150(3): p. 569-79.
  29. Wielgos, M.E., et al., Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors. Mol Cancer Res, 2017. 15(3): p. 340-347.
  30. Nowsheen, S., et al., Synthetic lethal interactions between EGFR and PARP inhibition in human triple negative breast cancer cells. PLoS One, 2012. 7(10): p. e46614.
  31. D'Amato, V., et al., Mechanisms of lapatinib resistance in HER2-driven breast cancer. Cancer Treat Rev, 2015. 41(10): p. 877-83.
  32. Hubalek, M., et al., Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment. Wien Med Wochenschr, 2010. 160(19-20): p. 506-12.
  33. Liu, L., et al., Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res, 2009. 69(17): p. 6871-8.
  34. Pohlmann, P.R., I.A. Mayer, and R. Mernaugh, Resistance to Trastuzumab in Breast Cancer. Clin Cancer Res, 2009. 15(24): p. 7479-7491.
  35. Shi, H., et al., Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms. Tumour Biol, 2016.
  36. Ruprecht, B., et al., Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis. Cancer Res, 2017. 77(8): p. 1842-1853.
  37. Campbell, K.J., et al., MCL-1 is a prognostic indicator and drug target in breast cancer. Cell Death Dis, 2018. 9(2): p. 19.
  38. Martin, A.P., et al., Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy. Cancer Biol Ther, 2009. 8(21): p. 2084-96.
  39. Eustace, A.J., et al., Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL. BMC Cancer, 2018. 18(1): p. 965.
  40. Bashari, M.H., et al., Mcl-1 confers protection of Her2-positive breast cancer cells to hypoxia: therapeutic implications. Breast Cancer Res, 2016. 18(1): p. 26.
  41. Campone, M., et al., c-Myc dependent expression of pro-apoptotic Bim renders HER2-overexpressing breast cancer cells dependent on anti-apoptotic Mcl-1. Mol Cancer, 2011. 10: p. 110.
  42. Williams, M.M., et al., Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers. Oncotarget, 2019. 10(52): p. 5389-5402.
  43. Hird, A.W. and A.E. Tron, Recent advances in the development of Mcl-1 inhibitors for cancer therapy. Pharmacol Ther, 2019. 198: p. 59-67.
  44. Merino, D., et al., Synergistic action of the MCL-1 inhibitor S63845 with current therapies in preclinical models of triple-negative and HER2-amplified breast cancer. Sci Transl Med, 2017. 9(401).
  45. Wielgos, M.E., et al., Trastuzumab-Resistant HER2(+) Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition. Mol Cancer Ther, 2018. 17(5): p. 921-930.

Cite this Article:

International Journal of Sciences is Open Access Journal.
This article is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) License.
Author(s) retain the copyrights of this article, though, publication rights are with Alkhaer Publications.

Search Articles

Issue December 2020

Volume 9, December 2020


Table of Contents



World-wide Delivery is FREE

Share this Issue with Friends:


Submit your Paper