Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

Anne M. van Harten, Marijke Buijze, Richard van der Mast, Martin A. Rooimans, Sanne R. Martens-de Kemp, Costa Bachas, Arjen Brink, Marijke Stigter-van Walsum, Rob M. F. Wolthuis, Ruud H. Brakenhoff

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Head and neck squamous cell carcinomas (HNSCCs) coincide with poor survival rates. The lack of driver oncogenes complicates the development of targeted treatments for HNSCC. Here, we follow-up on two previous genome-wide RNA and microRNA interference screens in HNSCC to cross-examine tumor-specific lethality by targeting ATM, ATR, CHEK1, or CHEK2. Our results uncover CHEK1 as the most promising target for HNSCC. CHEK1 expression is essential across a panel of HNSCC cell lines but redundant for growth and survival of untransformed oral keratinocytes and fibroblasts. LY2603618 (Rabusertib), which specifically targets Chk1 kinase, kills HNSCC cells effectively and specifically. Our findings show that HNSCC cells depend on Chk1-mediated signaling to progress through S-phase successfully. Chk1 inhibition coincides with stalled DNA replication, replication fork collapses, and accumulation of DNA damage. We further show that Chk1 inhibition leads to bimodal HNSCC cell killing. In the most sensitive cell lines, apoptosis is induced in S-phase, whereas more resistant cell lines manage to bypass replication-associated apoptosis, but accumulate chromosomal breaks that become lethal in subsequent mitosis. Interestingly, CDK1 expression correlates with treatment outcome. Moreover, sensitivity to Chk1 inhibition requires functional CDK1 and CDK4/6 to drive cell cycle progression, arguing against combining Chk1 inhibitors with CDK inhibitors. In contrast, Wee1 inhibitor Adavosertib progresses the cell cycle and thereby increases lethality to Chk1 inhibition in HNSCC cell lines. We conclude that Chk1 has become a key molecule in HNSCC cell cycle regulation and a very promising therapeutic target. Chk1 inhibition leads to S-phase apoptosis or death in mitosis. We provide a potential efficacy biomarker and combination therapy to follow-up in clinical setting.
Original languageEnglish
Article number38
JournalOncogenesis
Volume8
Issue number7
DOIs
Publication statusPublished - 1 Jul 2019

Cite this

van Harten, A. M., Buijze, M., van der Mast, R., Rooimans, M. A., Martens-de Kemp, S. R., Bachas, C., ... Brakenhoff, R. H. (2019). Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. Oncogenesis, 8(7), [38]. https://doi.org/10.1038/s41389-019-0147-x
van Harten, Anne M. ; Buijze, Marijke ; van der Mast, Richard ; Rooimans, Martin A. ; Martens-de Kemp, Sanne R. ; Bachas, Costa ; Brink, Arjen ; Stigter-van Walsum, Marijke ; Wolthuis, Rob M. F. ; Brakenhoff, Ruud H. / Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. In: Oncogenesis. 2019 ; Vol. 8, No. 7.
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title = "Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death",
abstract = "Head and neck squamous cell carcinomas (HNSCCs) coincide with poor survival rates. The lack of driver oncogenes complicates the development of targeted treatments for HNSCC. Here, we follow-up on two previous genome-wide RNA and microRNA interference screens in HNSCC to cross-examine tumor-specific lethality by targeting ATM, ATR, CHEK1, or CHEK2. Our results uncover CHEK1 as the most promising target for HNSCC. CHEK1 expression is essential across a panel of HNSCC cell lines but redundant for growth and survival of untransformed oral keratinocytes and fibroblasts. LY2603618 (Rabusertib), which specifically targets Chk1 kinase, kills HNSCC cells effectively and specifically. Our findings show that HNSCC cells depend on Chk1-mediated signaling to progress through S-phase successfully. Chk1 inhibition coincides with stalled DNA replication, replication fork collapses, and accumulation of DNA damage. We further show that Chk1 inhibition leads to bimodal HNSCC cell killing. In the most sensitive cell lines, apoptosis is induced in S-phase, whereas more resistant cell lines manage to bypass replication-associated apoptosis, but accumulate chromosomal breaks that become lethal in subsequent mitosis. Interestingly, CDK1 expression correlates with treatment outcome. Moreover, sensitivity to Chk1 inhibition requires functional CDK1 and CDK4/6 to drive cell cycle progression, arguing against combining Chk1 inhibitors with CDK inhibitors. In contrast, Wee1 inhibitor Adavosertib progresses the cell cycle and thereby increases lethality to Chk1 inhibition in HNSCC cell lines. We conclude that Chk1 has become a key molecule in HNSCC cell cycle regulation and a very promising therapeutic target. Chk1 inhibition leads to S-phase apoptosis or death in mitosis. We provide a potential efficacy biomarker and combination therapy to follow-up in clinical setting.",
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van Harten, AM, Buijze, M, van der Mast, R, Rooimans, MA, Martens-de Kemp, SR, Bachas, C, Brink, A, Stigter-van Walsum, M, Wolthuis, RMF & Brakenhoff, RH 2019, 'Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death' Oncogenesis, vol. 8, no. 7, 38. https://doi.org/10.1038/s41389-019-0147-x

Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. / van Harten, Anne M.; Buijze, Marijke; van der Mast, Richard; Rooimans, Martin A.; Martens-de Kemp, Sanne R.; Bachas, Costa; Brink, Arjen; Stigter-van Walsum, Marijke; Wolthuis, Rob M. F.; Brakenhoff, Ruud H.

In: Oncogenesis, Vol. 8, No. 7, 38, 01.07.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

AU - van Harten, Anne M.

AU - Buijze, Marijke

AU - van der Mast, Richard

AU - Rooimans, Martin A.

AU - Martens-de Kemp, Sanne R.

AU - Bachas, Costa

AU - Brink, Arjen

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AU - Wolthuis, Rob M. F.

AU - Brakenhoff, Ruud H.

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AB - Head and neck squamous cell carcinomas (HNSCCs) coincide with poor survival rates. The lack of driver oncogenes complicates the development of targeted treatments for HNSCC. Here, we follow-up on two previous genome-wide RNA and microRNA interference screens in HNSCC to cross-examine tumor-specific lethality by targeting ATM, ATR, CHEK1, or CHEK2. Our results uncover CHEK1 as the most promising target for HNSCC. CHEK1 expression is essential across a panel of HNSCC cell lines but redundant for growth and survival of untransformed oral keratinocytes and fibroblasts. LY2603618 (Rabusertib), which specifically targets Chk1 kinase, kills HNSCC cells effectively and specifically. Our findings show that HNSCC cells depend on Chk1-mediated signaling to progress through S-phase successfully. Chk1 inhibition coincides with stalled DNA replication, replication fork collapses, and accumulation of DNA damage. We further show that Chk1 inhibition leads to bimodal HNSCC cell killing. In the most sensitive cell lines, apoptosis is induced in S-phase, whereas more resistant cell lines manage to bypass replication-associated apoptosis, but accumulate chromosomal breaks that become lethal in subsequent mitosis. Interestingly, CDK1 expression correlates with treatment outcome. Moreover, sensitivity to Chk1 inhibition requires functional CDK1 and CDK4/6 to drive cell cycle progression, arguing against combining Chk1 inhibitors with CDK inhibitors. In contrast, Wee1 inhibitor Adavosertib progresses the cell cycle and thereby increases lethality to Chk1 inhibition in HNSCC cell lines. We conclude that Chk1 has become a key molecule in HNSCC cell cycle regulation and a very promising therapeutic target. Chk1 inhibition leads to S-phase apoptosis or death in mitosis. We provide a potential efficacy biomarker and combination therapy to follow-up in clinical setting.

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van Harten AM, Buijze M, van der Mast R, Rooimans MA, Martens-de Kemp SR, Bachas C et al. Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. Oncogenesis. 2019 Jul 1;8(7). 38. https://doi.org/10.1038/s41389-019-0147-x