Figure 5.

Clinical translation of Pol theta. a) A muscular dystrophy causing insertion mutation in the TCAP gene (TCAP^ins) can be corrected (TCAP^wt) through favoring of a specific repair product generated after cleavage with Cas9 (scissors) that is microhomology mediated (in red). b) Predictive biomarkers of Pol theta hyperactivity may help identify tumors that may be most vulnerable to Pol θ inhibition. Transcriptional upregulation of Pol θ and/or TMEJ-associated factors, measurement of TMEJ genomic scars (e.g., MHD or TINS), and presence of gene mutations that induce Pol theta dependency are candidate predictive biomarkers. A composite biomarker for TMEJ activity in tumors may be required for optimal patient selection. c) Pol θ has multiple functional sub-domains and molecular activities that can potentially be inhibited. These include helicase function (i.e., microhomology search), ATPase activity, and polymerase synthesis. The optimal domain for pharmacological targeting has not been determined. d) Pol θ inhibitors may be used in a variety of settings to improve cancer therapy. Preclinical studies support its investigation as monotherapy in highly selected tumors with strong dependency on Pol theta. Broader anti-tumor activity may be observed with combination therapy, particularly with DSB inducers, S phase damaging agents, and targeted therapy, including immunotherapy.