Identification of a novel chemotherapeutic agent specific for tumors with DNA mismatch

Abstract

Impairing the proliferation of rapidly dividing cancer cells is the primary mechanism for most conventional chemotherapeutic agents. However, cancer cells with DNA mismatch repair (MMR) deficiencies, such as Lynch Syndrome tumors, are resistant to most conventional chemotherapeutic agents since these cancer cells can continue to divide even with extensive DNA lesions. Here we have identified compound F as a small molecule that selectively kills MutSα-deficient cancer cells. Compound F binds preferentially to mismatched DNA and induces a DNA damage response in a mismatch repair-dependent manner. In MutSα-proficient cells, compound F binds to MutSα and induces dissociation of CHK2 from MutSα leading to S phase arrest and cell survival. In contrast, compound F-mismatched DNA adducts do not induce a DNA damage response in MutSα-deficient cells. Continued replication in the presence of compound F results in a high number of DNA double-strand breaks and ultimately leads to apoptosis of the MutSα-deficient cells. Consistently, compound F treatment specifically shrinks MutSα-deficient xenograft tumors. We believe that compound F offers the potential of an improved treatment option for patients with tumors with a DNA MMR deficiency.