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New study examining disruption of oncogenic pathways in mucoepidermoid carcinoma (MEC)

By Lynne Bingle Share this article

RESEARCH SPOTLIGHT:  New study examining disruption of oncogenic pathways in mucoepidermoid carcinoma (MEC)

Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumour (1,2) but can occur as a primary tumour in sites other than salivary glands, such as the lungs (3). Around 50 % of cases have an associated fusion gene; that is a newly expressed gene composed of parts of two normally unrelated genes. There are many different fusion genes expressed in our genome, mainly in cancers, and the one expressed by mucoepidermoid tumours is known as the CRTC1-MAML2 translocation.

CRTC1-MAML2 translocation

The CRTC1 gene normally results in the expression of a protein, the CREB transcription factor, that activates a number of genes associated with cell proliferation, cell survival, cell differentiation and apoptosis or programmed cell death (4).

It is important to remember that the fusion gene is not expressed by all mucoepidermoid tumours and even when present, not all cells in a tumour express the gene. In addition, we  do not yet know the exact consequences of the expression of the CRTC1-MAML2 gene and the resulting increased expression of CREB, however, it has been linked to cancer initiation and progression, increased chemo-resistance (cisplatin resistance) and lower survival of cancer patients (4-6).

Current treatments for this type of tumour include surgery and radiotherapy but this can have a significant impact on a patients’ quality of life. In addition, there is no current systemic therapy for MEC, including for those patients with unresectable tumours, or with disseminated disease. Currently available chemotherapy drugs for MEC are outdated and are mainly indicated as palliative management, with low response rates and consequently poor survival rates (7). If we had greater knowledge of the biology of the disease, including the true effects of the expression of the fusion gene, we might be able to better identify the tumour type and potentially suggest new treatments. Targeted inhibition of signalling pathways has been used successfully in the treatment of both breast (8) and prostate (9) cancers and we feel that the same rationale, in this case targeting the CREB pathway, needs to be followed for MEC.

The aim of this study 

The aim of the study by Pérez-de-Oliveira et al (10) was to determine the effects of CREB inhibition on MEC cell behaviour. This was done by adding a known CREB inhibitor, a drug named 666.15 (11), to cells which had originated from tumours which either did or did not express the fusion gene; we had two cell lines expressing the fusion gene (UM-HMC-2 and H292) and one which did not (H253) and directly compared results. Specifically, we studied the effect of CREB inhibition on cell survival and growth and the ability of the cells to invade tissues and migrate, which would potentially allow a tumour to metastasise.

The doses of CREB inhibitor needed to have an impact was relatively low, which is important for safety reasons, but we were also able to show that the dose required to impact proliferation of cells was much lower in the cells without the fusion gene. UM-HMC-2 was derived from a tumour of intermediate histological grade with perineural invasion while H292 was derived from a cervical lymph node metastasis of a pulmonary MEC. These cell lines represent MEC with the worst biological behaviour but we were able to demonstrate that 666.15 could control proliferation of these cells.

Our experiments not only demonstrated that 666.15 reduced cell proliferation as the drug affected the survival of fusion positive cells and also negatively impacted their ability to invade tissue; invasion is the first step in cell migration and metastasis. It has been established that motility of cells is reliant, to some extent, on the transition of cells from an epithelial type to a mesenchymal, or less specialised, type that have enhanced cell motility and invasiveness. E-cadherin is one of the most studied genes associated with this transition and reduced expression has been shown to increase cancer cell proliferation, invasiveness, and metastasis (12). In determining exactly how the 666.15 might impact migration and invasion of tissues by fusion positive cells we were able to demonstrate upregulation of E-cadherin on the UM-HMC-2 and H292, fusion positive, cells. This strongly suggests that CREB inhibition in MEC could impair cell functions associated with the metastatic process.

Conclusions

Overall, we have been able to demonstrate that inhibition of the CREB pathway in fusion positive cells reduced cancer associated behaviours but in comparing results from fusion positive and fusion negative cells we found that the effect of the drug was variable. This, in our opinion, endorses the current concept of personalized cancer therapy because each patient has unique features in their biological and molecular profile.

You can read the full paper 'Disruption of oncogenic pathways in mucoepidermoid carcinoma: CREB inhibitor 666.15 as a potential therapeutic agent' here.

 

References

  1. Alsanie I, Rajab S, Cottom H, Adegun O, Agarwal R, Jay, A et al. (2022) Distribution and frequency of salivary gland tumours: an international multicenter study. Head Neck Pathol, 16; 1043-1054. 10.1007/s12105-022-01459-0
  2. Quixabeira Oliveira GA, Pérez-de-Oliveira ME, Robinson L, Khurram SA, Hunter K, Speight PM et al. (2023) Epithelial salivary gland tumors in pediatric patients: an international collaborative study. Int J Pediatr Otorhinolaryngol 168 Article 111519. 10.1016/j.ijporl.2023.111519
  3. Huo Z, Wu H, Li J, Li S, Wu S, Liu Y et al. (2015) Primary pulmonary mucoepidermoid carcinoma: histopathological and molecular genetic studies of 26 cases. PLoS One, 10 (11) e0143169
  4. Steven A, Friedrich M, Jank P, Heimer N, Budczies J, Denkert C and Seliger B. (2020) What turns CREB on? And off? And why does it matter? Cell. Mol. Life Sci. 77, 4049-4067. 10.1007/s00018-020-03525-8
  5. Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H et al. (2005) Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation. EMBO J, 24(13); 2391-2402. 10.1038/sj.emboj.7600719
  6. Zhang L, Guo X, Zhang D, Fan Y, Qin L, Dong S and Zhang L. (2017) Upregulated miR-132 in Lgr5(+) gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. Mol. Carcinog. 56, 2022-2034. 10.1002/mc.22656
  7. Silva LC, Pérez-de-Oliveira ME, Pedroso CM, Leite AA, Santos-Silva AR, Lopes MA et al. (2023) Systemic therapies for salivary gland carcinomas: an overview of published clinical trials. Med Oral Patol Oral Cir Bucal. 27; 26264. 10.4317/medoral.26264
  8. Gonullu B, Angeli E, Pamoukdjian F and Bousquet G (2023), HER2 amplification level predicts pathological complete response in the neoadjuvant setting of HER2-overexpressing breast cancer: a meta-analysis and systematic review. Int J Mol Sci, 24; 3590. 10.3390/ijms24043590
  9. Sorrentino C and Di Carlo E. (2023) Molecular targeted therapies in metastatic prostate cancer: recent advances and future challenges. Cancers 15; 2885. 10.3390/cancers15112885
  10. Pérez‐de‐Oliveira ME, Wagner VP, Bingle CD, Vargas PA and Bingle L. (2024) Disruption of oncogenic pathways in mucoepidermoid carcinoma: CREB inhibitor 666.15 as a potential therapeutic agent. Oral Oncol. 159; 107029. doi: 10.1016/j.oraloncology.2024.107029.
  11. Xie F, Li BX, Kassenbrock A, Xue C, Wang X, Qian DZ et al. (2015) Identification of a potent inhibitor of CREB-mediated gene transcription with efficacious in vivo anticancer activity. J Med Chem, 58, 5075-5087. 10.1021/acs.jmedchem.5b00468
  12. Debnath P, Huirem RS, Dutta P, Palchaudhuri S. (2022) Epithelial-mesenchymal transition and its transcription factors. Biosci Rep,42; Article BSR20211754, 10.1042/BSR20211754

 

Last updated 08 April 2025