The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

Deborah R. Caswell; Philippe Gui; Manasi K. Mayekar; Emily K. Law; Oriol Pich; Chris Bailey; Jesse Boumelha; D. Lucas Kerr; Collin M. Blakely; Tadashi Manabe; Carlos Martinez-Ruiz; Bjorn Bakker; Juan De Dios Palomino Villcas; Natalie I. Vokes; Michelle Dietzen; Mihaela Angelova; Beatrice Gini; Whitney Tamaki; Paul Allegakoen; Wei Wu; Timothy J. Humpton; William Hill; Mona Tomaschko; Wei Ting Lu; Franziska Haderk; Maise Al Bakir; Ai Nagano; Francisco Gimeno-Valiente; Sophie de Carné Trécesson; Roberto Vendramin; Vittorio Barbè; Miriam Mugabo; Clare E. Weeden; Andrew Rowan; Caroline E. McCoach; Bruna Almeida; Mary Green; Carlos Gomez; Shigeki Nanjo; Dora Barbosa; Chris Moore; Joanna Przewrocka; James R.M. Black; Eva Grönroos; Alejandro Suarez-Bonnet; Simon L. Priestnall; Caroline Zverev; Scott Lighterness; James Cormack; Victor Olivas; Lauren Cech; Trisha Andrews; Brandon Rule; Yuwei Jiao; Xinzhu Zhang; Paul Ashford; Cameron Durfee; Subramanian Venkatesan; Nuri Alpay Temiz; Lisa Tan; Lindsay K. Larson; Prokopios P. Argyris; William L. Brown; Elizabeth A. Yu; Julia K. Rotow; Udayan Guha; Nitin Roper; Johnny Yu; Rachel I. Vogel; Nicholas J. Thomas; Antonio Marra; Pier Selenica; Helena Yu; Samuel F. Bakhoum; Su Kit Chew; Jorge S. Reis-Filho; Mariam Jamal-Hanjani; Karen H. Vousden; Nicholas McGranahan; Eliezer M. Van Allen; Nnennaya Kanu; Reuben S. Harris; Julian Downward; Trever G. Bivona; Charles Swanton

doi:10.1038/s41588-023-01592-8

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

Deborah R. Caswell, Philippe Gui, Manasi K. Mayekar, Emily K. Law, Oriol Pich, Chris Bailey, Jesse Boumelha, D. Lucas Kerr, Collin M. Blakely, Tadashi Manabe, Carlos Martinez-Ruiz, Bjorn Bakker, Juan De Dios Palomino Villcas, Natalie I. Vokes, Michelle Dietzen, Mihaela Angelova, Beatrice Gini, Whitney Tamaki, Paul Allegakoen, Wei WuTimothy J. Humpton, William Hill, Mona Tomaschko, Wei Ting Lu, Franziska Haderk, Maise Al Bakir, Ai Nagano, Francisco Gimeno-Valiente, Sophie de Carné Trécesson, Roberto Vendramin, Vittorio Barbè, Miriam Mugabo, Clare E. Weeden, Andrew Rowan, Caroline E. McCoach, Bruna Almeida, Mary Green, Carlos Gomez, Shigeki Nanjo, Dora Barbosa, Chris Moore, Joanna Przewrocka, James R.M. Black, Eva Grönroos, Alejandro Suarez-Bonnet, Simon L. Priestnall, Caroline Zverev, Scott Lighterness, James Cormack, Victor Olivas, Lauren Cech, Trisha Andrews, Brandon Rule, Yuwei Jiao, Xinzhu Zhang, Paul Ashford, Cameron Durfee, Subramanian Venkatesan, Nuri Alpay Temiz, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Elizabeth A. Yu, Julia K. Rotow, Udayan Guha, Nitin Roper, Johnny Yu, Rachel I. Vogel, Nicholas J. Thomas, Antonio Marra, Pier Selenica, Helena Yu, Samuel F. Bakhoum, Su Kit Chew, Jorge S. Reis-Filho, Mariam Jamal-Hanjani, Karen H. Vousden, Nicholas McGranahan, Eliezer M. Van Allen, Nnennaya Kanu, Reuben S. Harris, Julian Downward, Trever G. Bivona, Charles Swanton

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Abstract

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

Original language	English (US)
Pages (from-to)	60-73
Number of pages	14
Journal	Nature Genetics
Volume	56
Issue number	1
DOIs	https://doi.org/10.1038/s41588-023-01592-8
State	Published - Jan 2024

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Publisher Copyright:
© 2023, The Author(s).

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Caswell, D. R., Gui, P., Mayekar, M. K., Law, E. K., Pich, O., Bailey, C., Boumelha, J., Kerr, D. L., Blakely, C. M., Manabe, T., Martinez-Ruiz, C., Bakker, B., De Dios Palomino Villcas, J., I. Vokes, N., Dietzen, M., Angelova, M., Gini, B., Tamaki, W., Allegakoen, P., ... Swanton, C. (2024). The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance. Nature Genetics, 56(1), 60-73. https://doi.org/10.1038/s41588-023-01592-8

Caswell, DR, Gui, P, Mayekar, MK, Law, EK, Pich, O, Bailey, C, Boumelha, J, Kerr, DL, Blakely, CM, Manabe, T, Martinez-Ruiz, C, Bakker, B, De Dios Palomino Villcas, J, I. Vokes, N, Dietzen, M, Angelova, M, Gini, B, Tamaki, W, Allegakoen, P, Wu, W, Humpton, TJ, Hill, W, Tomaschko, M, Lu, WT, Haderk, F, Al Bakir, M, Nagano, A, Gimeno-Valiente, F, de Carné Trécesson, S, Vendramin, R, Barbè, V, Mugabo, M, Weeden, CE, Rowan, A, McCoach, CE, Almeida, B, Green, M, Gomez, C, Nanjo, S, Barbosa, D, Moore, C, Przewrocka, J, Black, JRM, Grönroos, E, Suarez-Bonnet, A, Priestnall, SL, Zverev, C, Lighterness, S, Cormack, J, Olivas, V, Cech, L, Andrews, T, Rule, B, Jiao, Y, Zhang, X, Ashford, P, Durfee, C, Venkatesan, S, Temiz, NA, Tan, L, Larson, LK, Argyris, PP, Brown, WL, Yu, EA, Rotow, JK, Guha, U, Roper, N, Yu, J, Vogel, RI, Thomas, NJ, Marra, A, Selenica, P, Yu, H, Bakhoum, SF, Chew, SK, Reis-Filho, JS, Jamal-Hanjani, M, Vousden, KH, McGranahan, N, Van Allen, EM, Kanu, N, Harris, RS, Downward, J, Bivona, TG & Swanton, C 2024, 'The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance', Nature Genetics, vol. 56, no. 1, pp. 60-73. https://doi.org/10.1038/s41588-023-01592-8

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abstract = "In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.",

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note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2024",

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doi = "10.1038/s41588-023-01592-8",

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AU - Gui, Philippe

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AU - Pich, Oriol

AU - Bailey, Chris

AU - Boumelha, Jesse

AU - Kerr, D. Lucas

AU - Blakely, Collin M.

AU - Manabe, Tadashi

AU - Martinez-Ruiz, Carlos

AU - Bakker, Bjorn

AU - De Dios Palomino Villcas, Juan

AU - I. Vokes, Natalie

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AU - Zverev, Caroline

AU - Lighterness, Scott

AU - Cormack, James

AU - Olivas, Victor

AU - Cech, Lauren

AU - Andrews, Trisha

AU - Rule, Brandon

AU - Jiao, Yuwei

AU - Zhang, Xinzhu

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AU - Durfee, Cameron

AU - Venkatesan, Subramanian

AU - Temiz, Nuri Alpay

AU - Tan, Lisa

AU - Larson, Lindsay K.

AU - Argyris, Prokopios P.

AU - Brown, William L.

AU - Yu, Elizabeth A.

AU - Rotow, Julia K.

AU - Guha, Udayan

AU - Roper, Nitin

AU - Yu, Johnny

AU - Vogel, Rachel I.

AU - Thomas, Nicholas J.

AU - Marra, Antonio

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AU - Yu, Helena

AU - Bakhoum, Samuel F.

AU - Chew, Su Kit

AU - Reis-Filho, Jorge S.

AU - Jamal-Hanjani, Mariam

AU - Vousden, Karen H.

AU - McGranahan, Nicholas

AU - Van Allen, Eliezer M.

AU - Kanu, Nnennaya

AU - Harris, Reuben S.

AU - Downward, Julian

AU - Bivona, Trever G.

AU - Swanton, Charles

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N2 - In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

AB - In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

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The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

Abstract

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