Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma

Shatha AbuHammad, Carleen Cullinane, Claire Martin, Zoe Bacolas, Teresa Ward, Huiqin Chen, Alison Slater, Kerry Ardley, Laura Kirby, Keefe T. Chan, Natalie Brajanovski, Lorey K. Smith, Aparna D. Rao, Emily J. Lelliott, Margarete Kleinschmidt, Ismael A. Vergara, Anthony T. Papenfuss, Peter Lau, Prerana Ghosh, Sue Haupt & 12 others Ygal Haupt, Elaine Sanij, Gretchen Poortinga, Richard B. Pearson, Hendrik Falk, David J. Curtis, Paul Stupple, Mark Devlin, Ian Street, Michael A. Davies, Grant A. McArthur, Karen E. Sheppard

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and welltolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/ 6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

Original languageEnglish
Pages (from-to)17990-18000
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number36
DOIs
Publication statusPublished - 3 Sep 2019

Keywords

  • Acquired resistance
  • CDK4
  • MDM4
  • p53
  • PRMT5

Cite this

AbuHammad, Shatha ; Cullinane, Carleen ; Martin, Claire ; Bacolas, Zoe ; Ward, Teresa ; Chen, Huiqin ; Slater, Alison ; Ardley, Kerry ; Kirby, Laura ; Chan, Keefe T. ; Brajanovski, Natalie ; Smith, Lorey K. ; Rao, Aparna D. ; Lelliott, Emily J. ; Kleinschmidt, Margarete ; Vergara, Ismael A. ; Papenfuss, Anthony T. ; Lau, Peter ; Ghosh, Prerana ; Haupt, Sue ; Haupt, Ygal ; Sanij, Elaine ; Poortinga, Gretchen ; Pearson, Richard B. ; Falk, Hendrik ; Curtis, David J. ; Stupple, Paul ; Devlin, Mark ; Street, Ian ; Davies, Michael A. ; McArthur, Grant A. ; Sheppard, Karen E. / Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 36. pp. 17990-18000.
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title = "Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma",
abstract = "Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and welltolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/ 6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.",
keywords = "Acquired resistance, CDK4, MDM4, p53, PRMT5",
author = "Shatha AbuHammad and Carleen Cullinane and Claire Martin and Zoe Bacolas and Teresa Ward and Huiqin Chen and Alison Slater and Kerry Ardley and Laura Kirby and Chan, {Keefe T.} and Natalie Brajanovski and Smith, {Lorey K.} and Rao, {Aparna D.} and Lelliott, {Emily J.} and Margarete Kleinschmidt and Vergara, {Ismael A.} and Papenfuss, {Anthony T.} and Peter Lau and Prerana Ghosh and Sue Haupt and Ygal Haupt and Elaine Sanij and Gretchen Poortinga and Pearson, {Richard B.} and Hendrik Falk and Curtis, {David J.} and Paul Stupple and Mark Devlin and Ian Street and Davies, {Michael A.} and McArthur, {Grant A.} and Sheppard, {Karen E.}",
year = "2019",
month = "9",
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language = "English",
volume = "116",
pages = "17990--18000",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "36",

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AbuHammad, S, Cullinane, C, Martin, C, Bacolas, Z, Ward, T, Chen, H, Slater, A, Ardley, K, Kirby, L, Chan, KT, Brajanovski, N, Smith, LK, Rao, AD, Lelliott, EJ, Kleinschmidt, M, Vergara, IA, Papenfuss, AT, Lau, P, Ghosh, P, Haupt, S, Haupt, Y, Sanij, E, Poortinga, G, Pearson, RB, Falk, H, Curtis, DJ, Stupple, P, Devlin, M, Street, I, Davies, MA, McArthur, GA & Sheppard, KE 2019, 'Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 36, pp. 17990-18000. https://doi.org/10.1073/pnas.1901323116

Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma. / AbuHammad, Shatha; Cullinane, Carleen; Martin, Claire; Bacolas, Zoe; Ward, Teresa; Chen, Huiqin; Slater, Alison; Ardley, Kerry; Kirby, Laura; Chan, Keefe T.; Brajanovski, Natalie; Smith, Lorey K.; Rao, Aparna D.; Lelliott, Emily J.; Kleinschmidt, Margarete; Vergara, Ismael A.; Papenfuss, Anthony T.; Lau, Peter; Ghosh, Prerana; Haupt, Sue; Haupt, Ygal; Sanij, Elaine; Poortinga, Gretchen; Pearson, Richard B.; Falk, Hendrik; Curtis, David J.; Stupple, Paul; Devlin, Mark; Street, Ian; Davies, Michael A.; McArthur, Grant A.; Sheppard, Karen E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 36, 03.09.2019, p. 17990-18000.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma

AU - AbuHammad, Shatha

AU - Cullinane, Carleen

AU - Martin, Claire

AU - Bacolas, Zoe

AU - Ward, Teresa

AU - Chen, Huiqin

AU - Slater, Alison

AU - Ardley, Kerry

AU - Kirby, Laura

AU - Chan, Keefe T.

AU - Brajanovski, Natalie

AU - Smith, Lorey K.

AU - Rao, Aparna D.

AU - Lelliott, Emily J.

AU - Kleinschmidt, Margarete

AU - Vergara, Ismael A.

AU - Papenfuss, Anthony T.

AU - Lau, Peter

AU - Ghosh, Prerana

AU - Haupt, Sue

AU - Haupt, Ygal

AU - Sanij, Elaine

AU - Poortinga, Gretchen

AU - Pearson, Richard B.

AU - Falk, Hendrik

AU - Curtis, David J.

AU - Stupple, Paul

AU - Devlin, Mark

AU - Street, Ian

AU - Davies, Michael A.

AU - McArthur, Grant A.

AU - Sheppard, Karen E.

PY - 2019/9/3

Y1 - 2019/9/3

N2 - Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and welltolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/ 6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

AB - Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and welltolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/ 6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.

KW - Acquired resistance

KW - CDK4

KW - MDM4

KW - p53

KW - PRMT5

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U2 - 10.1073/pnas.1901323116

DO - 10.1073/pnas.1901323116

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EP - 18000

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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