It is acknowledged that BCCs in in BCCNS owe their formation to a pre-existing mutagenic alteration in the PTCH1 gene, paired with a secondary mutation, such as one induced by UV exposure, occurring throughout an individual’s lifespan. Yet, emerging research implies that this secondary mutation facilitates the transformation of these cells into tumorous entities, but it does not provoke their proliferation or metastatic spread. One particular study (Chow et al)*. utilized RNA sequencing to decipher the biological pathway propelling BCC growth.


From the assay results, it was observed that BCCs exhibited a considerable amplification in the expression of the mTOR pathway. This pathway plays an essential role in regulating angiogenesis, the growth of new blood vessels from pre-existing ones. Thus, indicates that it is the heightened activity of the mTOR pathway, and the consequent enhancement of angiogenesis, that stimulates growth, rather than the initial PTCH1 mutation.


Further in the same study, the team pursued an investigation into whether the mTOR pathway’s inhibition would obstruct the HH pathway and tumor growth. This was executed by treating murine BCCs with three recognized mTOR inhibitors. The outcome of this part of the study revealed that all three mTOR inhibitors significantly reduced BCC growth over time.

Itraconazole is a known inhibitor of the mTOR pathway. The mechanistic target of mTOR is a protein kinase regulating cell growth, survival, metabolism, and immunity (Hua et al)**. It is identified that the major target of itraconazole in endothelial cells is VDAC1. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in HUVEC. Inhibition of VDAC1 by itraconazole leads to an increase in cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity (Head et al)***.


In their testing it was found that by using a phenotypical approach starting with the effect of itraconazole the G1-S cell cycle transition of the endothelial cells, itraconazole specifically inhibited the mTOR signaling pathway by downregulating the kinase activity of mTORC1.

Treatment of BCCNS with Itraconazole



* Rachel Y. Chow, Taylor M. Levee, Gurleen Kaur, Daniel P. Cedeno, Linda T. Doan, Scott X. Atwood bioRxiv 2020.08.24.264598; doi:


** Hua, H., Kong, Q., Zhang, H. et al. Targeting mTOR for cancer therapy. J Hematol Oncol12, 71 (2019).


*** Head SA, Shi W, Zhao L, Gorshkov K, Pasunooti K, Chen Y, Deng Z, Li RJ, Shim JS, Tan W, Hartung T, Zhang J, Zhao Y, Colombini M, Liu JO. Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells. Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):E7276-85. doi: 10.1073/pnas.1512867112. Epub 2015 Dec 10. PMID: 26655341; PMCID: PMC4703001.