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Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer

View ORCID ProfileHajrah Khawaja, Rebecca Briggs, Cheryl Latimer, Md A.M.B. Rassel, Daryl Griffin, Lyndsey Hanson, View ORCID ProfileAlberto Bardelli, Frederica Di Nicolantonio, Simon McDade, Christopher J. Scott, Shauna Lambe, Manisha Maurya, View ORCID ProfileAndreas Lindner, Jochen H.M. Prehn, Jose Sousa, Chris Winnington, Melissa J. LaBonte, Sarah Ross, Sandra Van Schaeybroeck
doi: https://doi.org/10.1101/2022.05.10.491367
Hajrah Khawaja
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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  • ORCID record for Hajrah Khawaja
Rebecca Briggs
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Cheryl Latimer
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Md A.M.B. Rassel
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Daryl Griffin
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Lyndsey Hanson
2AstraZeneca, Cambridge, CB2 0RE, United Kingdom
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Alberto Bardelli
3Department of Oncology, University of Torino, Candiolo (TO) 10060, Italy
4Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO) 10060, Italy
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Frederica Di Nicolantonio
3Department of Oncology, University of Torino, Candiolo (TO) 10060, Italy
4Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO) 10060, Italy
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Simon McDade
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Christopher J. Scott
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Shauna Lambe
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Manisha Maurya
5Precision Medicine Centre of Excellence, Health Sciences Building, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Andreas Lindner
6Centre of Systems Medicine; Royal College of Surgeons in Ireland University of Medicine and Health Sciences, 123□St. Stephen’s Green, Dublin 2, Ireland
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Jochen H.M. Prehn
6Centre of Systems Medicine; Royal College of Surgeons in Ireland University of Medicine and Health Sciences, 123□St. Stephen’s Green, Dublin 2, Ireland
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Jose Sousa
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
7Personal Health Data Science Group, Sano. Centre for Computational Personalised Medicine, Krakow, Poland
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Chris Winnington
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Melissa J. LaBonte
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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Sarah Ross
2AstraZeneca, Cambridge, CB2 0RE, United Kingdom
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Sandra Van Schaeybroeck
1Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7AE, United Kingdom
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  • For correspondence: s.vanschaeybroeck@qub.ac.uk
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ABSTRACT

Purpose Novel covalent inhibitors of KRASG12C have shown limited response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed.

Experimental design Small molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo. AZ’1569-resistant CRC cells were generated and characterised.

Results Response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as single-agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12CMT xenografts. Finally, AZ’1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification.

Conclusions Combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients.

Competing Interest Statement

Sarah Ross & Lyndsey Hanson were/are employees and shareholders of AstraZeneca. The other authors declare that they have no conflict of interest.

Footnotes

  • Financial support: Cancer Research UK (C212/A7402); MErCuRIC, funded by the European Commission’s Framework Programme 7, under contract #602901; Tom Simms Memorial Fund in Queen’s University Belfast; sponsored research agreement from Astra Zeneca; Science Foundation Ireland and the Health Research Board (16/US/3301).

  • Conflicts of interest: Sarah Ross & Lyndsey Hanson were/are employees and shareholders of AstraZeneca. The other authors declare that they have no conflict of interest.

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE198530

  • https://eur02.safelinks.protection.outlook.com/?url=%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fbioproject%2F815942&data=04%7C01%7CH.Khawaja%40qub.ac.uk%7Cff0dc5d74e48464dc0ca08da05a17a12%7Ceaab77eab4a549e3a1e8d6dd23a1f286%7C0%7C0%7C637828488513915676%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C2000&sdata=LvT3AeKHbh7FCsesGA9JE9Jl4nDwrOT8dWLKV1SCkjA%3D&reserved=0

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer
Hajrah Khawaja, Rebecca Briggs, Cheryl Latimer, Md A.M.B. Rassel, Daryl Griffin, Lyndsey Hanson, Alberto Bardelli, Frederica Di Nicolantonio, Simon McDade, Christopher J. Scott, Shauna Lambe, Manisha Maurya, Andreas Lindner, Jochen H.M. Prehn, Jose Sousa, Chris Winnington, Melissa J. LaBonte, Sarah Ross, Sandra Van Schaeybroeck
bioRxiv 2022.05.10.491367; doi: https://doi.org/10.1101/2022.05.10.491367
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Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer
Hajrah Khawaja, Rebecca Briggs, Cheryl Latimer, Md A.M.B. Rassel, Daryl Griffin, Lyndsey Hanson, Alberto Bardelli, Frederica Di Nicolantonio, Simon McDade, Christopher J. Scott, Shauna Lambe, Manisha Maurya, Andreas Lindner, Jochen H.M. Prehn, Jose Sousa, Chris Winnington, Melissa J. LaBonte, Sarah Ross, Sandra Van Schaeybroeck
bioRxiv 2022.05.10.491367; doi: https://doi.org/10.1101/2022.05.10.491367

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