MLH1 and MSH2 as a Target for BLBC Therapy

Daniel Koppel

Authors:  Mo Jiao, Daniel Koppel

Faculty Mentor:  Mo Jiao

Department:  College of Medicine

Abstract

Single nucleotide misincorporation and small insertion/deletion loops during DNA replication are corrected by mismatch proteins. Mismatches are recognized by the MSH2/6 heterodimer MutSα, which recruits several effector complexes, including MutLα, a heterodimer of MLH1 and PMS2. Mutations in mismatch repair genes lead to Lynch Syndrome, which can result in hereditary non-polyposis colorectal cancer. Despite being an effective tumor suppressor, this pathway is sensitive to synthetic lethality, which entails a delicate balance between clonal evolution and cell death. Thus, these proteins have emerged as potential targets to treat basal-like breast cancer (BLBC). Genetic deletion of MSH2/MLH1 may lead to the killing of cancer cells via accumulated genetic damage, neoantigen boosted immune recognition, and sensitization to subsequent immunotherapy. This was tested by knocking out MLH1 or MSH2 in BLBC cell lines 4T1 and PY8119 through CRISPR/Cas9. Knockout clones of 4T1 were combined and injected into the right flank of the 5th pair of mammals of Balb/c mice, while the PY8119 clones were injected into C57BL/6 mice. MLH1 deficiency promoted tumor growth and lung metastasis, while MSH2 knockout reduced lung metastasis, but did not alter primary tumor size. These results suggest MSH2 as a synthetic lethality candidate that is worthy of further investigation.

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Marina Curtis
Marina Curtis (@guest_6182)
1 year ago

As the use of CRISPR/Cas9 on human genes is highly controversial, even for somatic cells, would this potentially be applied in a way that one could frame as targeting “cancer” cells instead of “human” cells?

Daniel Koppel
Daniel Koppel (@guest_6468)
1 year ago

Hey Marina,

In terms of human applications, that is still far off, and this is just a preliminary study. While CRISPR/Cas9 could be used to eliminate these genes in cancer cells, inhibitors of the protein products could also be used. However, you are definitely correct, but using it for cancer treatment I believe is ethical.