Table 6 Biomarker and therapeutic potential of APOBEC3s

Biomarker: Predict strong responsiveness

Therapeutic strategy: Activation of APOBEC3s to sensitize tumor cells to treatment

Immunotherapy

Better response to immune checkpoint blockade therapy in bladder, HNSCC, breast, and lung cancer

Mutation burden and expression

[37, 160, 166, 174, 180, 181]

Increased PD-L1 expression

Expression (3B)

[36]

Higher PD-L1 and PD-L2 levels in glioma

Expression

[51]

Slightly higher sPD-L levels in breast cancer

Expression (3A)

[64]

A3A, A3D, and A3H correlated with PD-L1 on tumor-infiltrating immune cells, and A3F associated with more PD-L1 on tumor cells

Expression (3A, 3D, 3H, and 3F)

[171]

APOBEC3 overexpression and APOBEC3-induced kataegis positively correlated with PD-L1 expression

In vitro overexpression

[189]

Correlation with PD-L1 expression due to induction of PD-L1 via JNK/c-JUN signaling

In vitro overexpression, mutation burden and expression (3A)

[190]

Increased immune checkpoint blockade responsiveness in a melanoma model

In vivo overexpression (3B)

[187]

Improved response to anti-CTLA-4 therapy in a HER2-driven breast cancer model

In vivo overexpression

[164]

Platinum-based chemotherapy

Better survival in bladder cancer, which is often treated with cisplatin**

Mutation burden and expression

[46, 61, 170]

Improved outcomes in ovarian cancer, which is typically treated with cisplatin or carboplatin**

Mutation burden and expression

[41, 167, 186]

Increased response to cisplatin in breast cancer cells

In vitro overexpression

[188]

DDR inhibitors

Increased responsiveness to ATR and Chk1/2 inhibitors in leukemia cells

In vitro overexpression (3A)

[52]

Higher sensitivity to ATR and Chk1/2 inhibition

In vitro overexpression

[191]

Greater sensitivity to CHEK1/2 PARP, and WEE1 inhibition in p53-defecient T cells

In vitro overexpression

[99]

Enhanced sensitivity to PARP inhibitors in pancreatic cancer cells

In vitro overexpression (3A)

[157]

Tumors with DNA repair deficits

Induction of apoptosis, likely due to high levels of DNA damage

In vitro overexpression (3A)

[43]

Biomarker: Predict resistance

Therapeutic strategy: Inhibition of APOBEC3s to promote therapeutic response or delay resistance

Rapidly evolving tumors

APOBEC3s identified as drivers of tumor heterogeneity and subclonal evolution

N/A

[82]

APOBEC3-induced subclonal driver mutations in pan-cancer analysis

N/A

[148]

EGFR inhibitors

APOBEC3s may induce the T790M mutation that confers resistance to EGFR inhibitors in lung cancer

N/A

[82, 141]

Raf inhibitors

Poor response to Raf inhibitors in glioma

Expression

[51]

APOBEC3-induced mutations may decrease response to Raf inhibitors in multiple myeloma

N/A

[158]

APOBEC3-induced MKE2 L46F promotes resistance to BRAF inhibitors in melanoma

N/A

[82, 142]

Akt inhibitors

Increased Akt-mediated anoikis inhibition

In vitro overexpression

[49]

Endocrine therapies

Accelerated resistance to tamoxifen in breast cancer cells through a catalytic mechanism

In vitro overexpression

[192]

Oncolytic virotherapy

Escape from vesicular stomatitis virus therapy in melanoma models

In vitro and in vivo overexpression

[193]

Decreased efficacy of oncolytic virus therapy

In vitro and in vivo overexpression

[194]

Recurrent APOBEC3-induced mutations un resistant cells

In vitro and in vivo overexpression

[187]