3.4. Effects of Defective TFIIH on Carcinogenesis and Cancer
Treatment
As TFIIH plays a critical role in maintaining genome stability, cells
with defective TFIIH are more likely to have high genome instability,
which may further elevate cancer risk. Indeed, somatic mutations in the
XPD gene, which is also named ERCC2, have been widely observed in
tumors, such as bladder and urothelial cancers (Kim et al., 2016).
Tumors of the urothelial tract and bladder are associated with exposure
to tobacco and other DNA damaging chemicals that induce bulky lesions
(Freedman et al., 2011; Ploeg et al., 2009). Lack of TFIIH may render
the exposed cells more vulnerable to these damaging agents, thereby
promoting genome instability and tumor growth. Additionally, it has been
shown that somatic mutations in XPD are associated with a distinct
genomic signature in urothelial tumors, signature 5*, which closely
resembles COSMIC signature 5 (Kim et al., 2016). There is also evidence
indicating a correlation between signature 5* and smoking (Kim et al.,
2016), which suggests that low repair of tobacco-induced DNA damage in
XPD-mutated cancer cells may drive this unique mutation signature. On
the other hand, somatic mutations in XPD also represent an intrinsic
vulnerability of the tumor cells to various therapies. This idea has
been tested in bladder cancer, in which XPD somatic mutations are
frequently found. The published data shows that many clinically observed
XPD mutations enhance sensitivity to cisplatin in cancer cell lines and
mouse xenograft models (Q. Li et al., 2019).
Another common mutation site is in the CDK7 subunit of the CAK complex
of TFIIH. Mutations in this subunit are associated with triple negative
breast cancer, peripheral T-cell lymphomas, and ovarian cancer.
Preclinical models have shown that the use of CDK7 inhibitors reduces
drug resistance in human cells and mouse models (Rimel & Taatjes,
2018).