MTOR promotes basal cell carcinoma growth through atypical PKC

Abstract

Advanced basal cell carcinomas (BCCs) are driven by the Hedgehog (HH) pathway and often possess inherent resistance to SMO inhibitors. Identifying and targeting pathways that bypass SMO could provide alternative treatments for patients with advanced or metastatic BCC. Here, we use a combination of RNA-sequencing analysis of advanced human BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify an MTOR expression signature in BCC. Pharmacological inhibition of MTOR activity in BCC cells significantly reduces cell proliferation without affecting HH signaling. Similarly, treatment of the Ptch1fl/fl; Gli1-CreERT2 mouse BCC tumor model with everolimus reduces tumor growth. aPKC, a downstream target of MTOR, shows reduced activity, suggesting that MTOR promotes tumor growth by activating aPKC and demonstrating that suppressing MTOR could be a promising target for BCC patients.

PI3K Promotes Basal Cell Carcinoma Growth Through Kinase-Induced p21 Degradation

“…Another possibility could be that higher in vivo dosage of drug could eventually suppress HH signaling, although the current dosage is able to inhibit tumor growth. Nevertheless, PI3K likely operates downstream or in parallel to the HH pathway in BCC, similar to our results for MTOR in Ptch1 fl/fl ; Gli1-Cre ERT2 BCCs ( 48 ) and consistent with models where MTOR acts downstream of the HH pathway in Ptch1 +/− / SKH-1 BCCs ( 60 ).…”

“…Histological staining of the dorsal skin of BKM120-treated mice showed a significant reduction in total tumor size compared to DMSO controls ( Figures 4A, B ). Interestingly, Gli1 protein expression was not altered in BKM120-treated mice ( Figures 4C, D ), suggesting that the PI3K operates downstream or in parallel to the HH pathway in vivo , a result that is similar to Mtor inhibition ( 48 ). The discrepancy between our in vitro and in vivo results may indicate that the tumor microenvironment alters how the PI3K pathway functions in relation to the HH pathway.…”

“…To assess alternative pathways that may drive BCC tumor growth, we reanalyzed our bulk-level RNA-sequencing (RNA-seq) data of 14 matched tumor-normal pairs of advanced and SMO inhibitor-resistant BCC samples ( 22 , 48 ). Differential gene expression analysis across the 14 tumor-normal pairs identified 1602 genes that were upregulated by two-fold or more in the resistant BCC tumors compared to their normal skin counterparts ( 48 ).…”

“…To assess alternative pathways that may drive BCC tumor growth, we reanalyzed our bulk-level RNA-sequencing (RNA-seq) data of 14 matched tumor-normal pairs of advanced and SMO inhibitor-resistant BCC samples ( 22 , 48 ). Differential gene expression analysis across the 14 tumor-normal pairs identified 1602 genes that were upregulated by two-fold or more in the resistant BCC tumors compared to their normal skin counterparts ( 48 ). Database analysis of the upregulated genes with the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed the expected upregulation of the cell cycle, HH pathway, and BCC-associated genes ( Figure 1A , Supplementary Data 1 ).…”

“…In addition to the present study showing BKM120 efficacy on Ptch1 fl/fl ; Gli1-Cre ERT2 BCCs, inhibition of the PI3K/AKT/MTOR pathway has been shown to suppress irradiated Ptch1 +/- ; Krt14 CreER2 ; p53 fl/fl BCCs with XL765, but not XL147 or GDC-0941 ( 64 ). In addition, suppressing MTOR activity using everolimus can suppress Ptch1 fl/fl ; Gli1-Cre ERT2 BCCs through an aPKC-dependent process ( 48 ) and has been used in the clinic for compassionate treatment of BCCs in elderly patients who refused surgery and did not respond to alternative treatments ( 65 ). Combination therapy may also be crucial to treat advanced BCC patients.…”