Novel small molecule inhibitors expose cancer therapeutic vulnerabilties

Cancer resistance to therapy remains the most challenging aspect of treatment and cure. Dysfunction in several critical cellular pathways causes resistance to chemotherapeutics. However, one common theme within the pathways causing cancer resistance is increased mutation formation. One major pathway for cancer cells to produce mutations is the Translesion Synthesis (TLS) process. TLS is a DNA damage bypass process, where specialized polymerases replicate over damaged DNA. Unrepaired DNA damage stalls replication, which is a cellular response to arrest the cell cycle and repair the damage. However, cancer cells utilize the same strategy by bypassing or replicating over DNA damages from the cancer drugs. Therefore, limiting translesion synthesis is an ideal strategy for suppressing cancer resistance.