Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

Sebastijan Hobor; Maise Al Bakir; Crispin T. Hiley; Marcin Skrzypski; Alexander M. Frankell; Bjorn Bakker; Thomas B.K. Watkins; Aleksandra Markovets; Jonathan R. Dry; Andrew P. Brown; Jasper van der Aart; Hilda van den Bos; Diana Spierings; Dahmane Oukrif; Marco Novelli; Turja Chakrabarti; Adam H. Rabinowitz; Laila Ait Hassou; Saskia Litière; D. Lucas Kerr; Lisa Tan; Gavin Kelly; David A. Moore; Matthew J. Renshaw; Subramanian Venkatesan; William Hill; Ariana Huebner; Carlos Martínez-Ruiz; James R.M. Black; Wei Wu; Mihaela Angelova; Nicholas McGranahan; Julian Downward; Juliann Chmielecki; Carl Barrett; Kevin Litchfield; Su Kit Chew; Collin M. Blakely; Elza C. de Bruin; Floris Foijer; Karen H. Vousden; Trever G. Bivona; TRACERx Consortium

doi:10.1038/s41467-024-47606-9

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

Sebastijan Hobor, Maise Al Bakir, Crispin T. Hiley, Marcin Skrzypski, Alexander M. Frankell, Bjorn Bakker, Thomas B.K. Watkins, Aleksandra Markovets, Jonathan R. Dry, Andrew P. Brown, Jasper van der Aart, Hilda van den Bos, Diana Spierings, Dahmane Oukrif, Marco Novelli, Turja Chakrabarti, Adam H. Rabinowitz, Laila Ait Hassou, Saskia Litière, D. Lucas KerrLisa Tan, Gavin Kelly, David A. Moore, Matthew J. Renshaw, Subramanian Venkatesan, William Hill, Ariana Huebner, Carlos Martínez-Ruiz, James R.M. Black, Wei Wu, Mihaela Angelova, Nicholas McGranahan, Julian Downward, Juliann Chmielecki, Carl Barrett, Kevin Litchfield, Su Kit Chew, Collin M. Blakely, Elza C. de Bruin, Floris Foijer, Karen H. Vousden, Trever G. Bivona, TRACERx Consortium

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Original language	English
Article number	4871
Journal	Nature Communications
Volume	15
Issue	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-024-47606-9
Publication status	Published - Dec 2024

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Hobor, S., Al Bakir, M., Hiley, C. T., Skrzypski, M., Frankell, A. M., Bakker, B., Watkins, T. B. K., Markovets, A., Dry, J. R., Brown, A. P., van der Aart, J., van den Bos, H., Spierings, D., Oukrif, D., Novelli, M., Chakrabarti, T., Rabinowitz, A. H., Ait Hassou, L., Litière, S., ... TRACERx Consortium (2024). Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. Nature Communications, 15(1), Article 4871. https://doi.org/10.1038/s41467-024-47606-9

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title = "Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling",

abstract = "The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.",

author = "Sebastijan Hobor and {Al Bakir}, Maise and Hiley, {Crispin T.} and Marcin Skrzypski and Frankell, {Alexander M.} and Bjorn Bakker and Watkins, {Thomas B.K.} and Aleksandra Markovets and Dry, {Jonathan R.} and Brown, {Andrew P.} and {van der Aart}, Jasper and {van den Bos}, Hilda and Diana Spierings and Dahmane Oukrif and Marco Novelli and Turja Chakrabarti and Rabinowitz, {Adam H.} and {Ait Hassou}, Laila and Saskia Liti{\`e}re and Kerr, {D. Lucas} and Lisa Tan and Gavin Kelly and Moore, {David A.} and Renshaw, {Matthew J.} and Subramanian Venkatesan and William Hill and Ariana Huebner and Carlos Mart{\'i}nez-Ruiz and Black, {James R.M.} and Wei Wu and Mihaela Angelova and Nicholas McGranahan and Julian Downward and Juliann Chmielecki and Carl Barrett and Kevin Litchfield and Chew, {Su Kit} and Blakely, {Collin M.} and {de Bruin}, {Elza C.} and Floris Foijer and Vousden, {Karen H.} and Bivona, {Trever G.} and Lester, {Jason F.} and Amrita Bajaj and Apostolos Nakas and Azmina Sodha-Ramdeen and Mohamad Tufail and Birkbak, {Nicolai J.} and Judit Kisistok and Mateo Sokac and {TRACERx Consortium}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-47606-9",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

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Hobor, S, Al Bakir, M, Hiley, CT, Skrzypski, M, Frankell, AM, Bakker, B, Watkins, TBK, Markovets, A, Dry, JR, Brown, AP, van der Aart, J, van den Bos, H, Spierings, D, Oukrif, D, Novelli, M, Chakrabarti, T, Rabinowitz, AH, Ait Hassou, L, Litière, S, Kerr, DL, Tan, L, Kelly, G, Moore, DA, Renshaw, MJ, Venkatesan, S, Hill, W, Huebner, A, Martínez-Ruiz, C, Black, JRM, Wu, W, Angelova, M, McGranahan, N, Downward, J, Chmielecki, J, Barrett, C, Litchfield, K, Chew, SK, Blakely, CM, de Bruin, EC, Foijer, F, Vousden, KH, Bivona, TG & TRACERx Consortium 2024, 'Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling', Nature Communications, vol. 15, no. 1, 4871. https://doi.org/10.1038/s41467-024-47606-9

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling. / Hobor, Sebastijan; Al Bakir, Maise; Hiley, Crispin T. et al.
In: Nature Communications, Vol. 15, No. 1, 4871, 12.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

AU - Hobor, Sebastijan

AU - Al Bakir, Maise

AU - Hiley, Crispin T.

AU - Skrzypski, Marcin

AU - Frankell, Alexander M.

AU - Bakker, Bjorn

AU - Watkins, Thomas B.K.

AU - Markovets, Aleksandra

AU - Dry, Jonathan R.

AU - Brown, Andrew P.

AU - van der Aart, Jasper

AU - van den Bos, Hilda

AU - Spierings, Diana

AU - Oukrif, Dahmane

AU - Novelli, Marco

AU - Chakrabarti, Turja

AU - Rabinowitz, Adam H.

AU - Ait Hassou, Laila

AU - Litière, Saskia

AU - Kerr, D. Lucas

AU - Tan, Lisa

AU - Kelly, Gavin

AU - Moore, David A.

AU - Renshaw, Matthew J.

AU - Venkatesan, Subramanian

AU - Hill, William

AU - Huebner, Ariana

AU - Martínez-Ruiz, Carlos

AU - Black, James R.M.

AU - Wu, Wei

AU - Angelova, Mihaela

AU - McGranahan, Nicholas

AU - Downward, Julian

AU - Chmielecki, Juliann

AU - Barrett, Carl

AU - Litchfield, Kevin

AU - Chew, Su Kit

AU - Blakely, Collin M.

AU - de Bruin, Elza C.

AU - Foijer, Floris

AU - Vousden, Karen H.

AU - Bivona, Trever G.

AU - Lester, Jason F.

AU - Bajaj, Amrita

AU - Nakas, Apostolos

AU - Sodha-Ramdeen, Azmina

AU - Tufail, Mohamad

AU - Birkbak, Nicolai J.

AU - Kisistok, Judit

AU - Sokac, Mateo

AU - TRACERx Consortium

PY - 2024/12

Y1 - 2024/12

N2 - The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

AB - The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

UR - http://www.scopus.com/inward/record.url?scp=85196137928&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-47606-9

DO - 10.1038/s41467-024-47606-9

M3 - Journal article

C2 - 38871738

AN - SCOPUS:85196137928

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4871

ER -

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

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