TY - JOUR
T1 - Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer
AU - Petljak, Mia
AU - Green, Abby M.
AU - Maciejowski, John
AU - Weitzman, Matthew D.
N1 - Funding Information:
M.P.’s research was supported by the European Molecular Biology Organization Long-Term Fellowship (ALTF 760–2019) and is supported by the National Cancer Institute (NCI) (CA270102). J.M.’s laboratory is supported by the NCI (CA212290, CA008748, CA261183, CA270102), the Pew Charitable Trusts, the V Foundation, the Starr Cancer Consortium, the Emerald Foundation and the Geoffrey Beene and Ludwig Centers at the MSKCC. A.M.G.’s laboratory is supported by the NCI (K08CA21299), the Department of Defense (CA2000867), the American Cancer Society, the Cancer Research Foundation and the Children’s Discovery Institute. Research on APOBEC enzymes in the laboratory of M.D.W. was supported by grants from the National Institutes of Health (CA181259 and CA185799). We thank M. O’Reilly and E. Berg from the Broad Institute’s Pattern team for figure graphics.
Funding Information:
M.P.’s research was supported by the European Molecular Biology Organization Long-Term Fellowship (ALTF 760–2019) and is supported by the National Cancer Institute (NCI) (CA270102). J.M.’s laboratory is supported by the NCI (CA212290, CA008748, CA261183, CA270102), the Pew Charitable Trusts, the V Foundation, the Starr Cancer Consortium, the Emerald Foundation and the Geoffrey Beene and Ludwig Centers at the MSKCC. A.M.G.’s laboratory is supported by the NCI (K08CA21299), the Department of Defense (CA2000867), the American Cancer Society, the Cancer Research Foundation and the Children’s Discovery Institute. Research on APOBEC enzymes in the laboratory of M.D.W. was supported by grants from the National Institutes of Health (CA181259 and CA185799). We thank M. O’Reilly and E. Berg from the Broad Institute’s Pattern team for figure graphics.
Publisher Copyright:
© 2022, Springer Nature America, Inc.
PY - 2022/11
Y1 - 2022/11
N2 - Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half of cancer types, including some therapy-resistant and metastatic tumors. Driver mutations can occur in APOBEC3-favored sequence contexts, suggesting that mutagenesis by APOBEC3 enzymes may drive cancer evolution. The APOBEC3-mediated signatures are often detected in subclonal branches of tumor phylogenies and are acquired in cancer cell lines over long periods of time, indicating that APOBEC3 mutagenesis can be ongoing in cancer. Collectively, these and other observations have led to the proposal that APOBEC3 mutagenesis represents a disease-modifying process that could be inhibited to limit tumor heterogeneity, metastasis and drug resistance. However, critical aspects of APOBEC3 biology in cancer and in healthy tissues have not been clearly defined, limiting well-grounded predictions regarding the benefits of inhibiting APOBEC3 mutagenesis in different settings in cancer. We discuss the relevant mechanistic gaps and strategies to address them to investigate whether inhibiting APOBEC3 mutagenesis may confer clinical benefits in cancer.
AB - Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half of cancer types, including some therapy-resistant and metastatic tumors. Driver mutations can occur in APOBEC3-favored sequence contexts, suggesting that mutagenesis by APOBEC3 enzymes may drive cancer evolution. The APOBEC3-mediated signatures are often detected in subclonal branches of tumor phylogenies and are acquired in cancer cell lines over long periods of time, indicating that APOBEC3 mutagenesis can be ongoing in cancer. Collectively, these and other observations have led to the proposal that APOBEC3 mutagenesis represents a disease-modifying process that could be inhibited to limit tumor heterogeneity, metastasis and drug resistance. However, critical aspects of APOBEC3 biology in cancer and in healthy tissues have not been clearly defined, limiting well-grounded predictions regarding the benefits of inhibiting APOBEC3 mutagenesis in different settings in cancer. We discuss the relevant mechanistic gaps and strategies to address them to investigate whether inhibiting APOBEC3 mutagenesis may confer clinical benefits in cancer.
UR - http://www.scopus.com/inward/record.url?scp=85140402741&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01196-8
DO - 10.1038/s41588-022-01196-8
M3 - Article
C2 - 36280735
AN - SCOPUS:85140402741
SN - 1061-4036
VL - 54
SP - 1599
EP - 1608
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -