Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance

Claire A. Martin, Carleen Cullinane, Laura Kirby, Shatha Abuhammad, Emily J. Lelliott, Kelly Waldeck, Richard J. Young, Natalie Brajanovski, Donald P. Cameron, Rachael Walker, Elaine Sanij, Gretchen Poortinga, Ross D. Hannan, Richard B. Pearson, Rodney J. Hicks, Grant A. McArthur, Karen E. Sheppard

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug-tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors.

Original languageEnglish
Pages (from-to)2139-2152
Number of pages14
JournalInternational Journal of Cancer
Volume142
Issue number10
DOIs
Publication statusPublished - 15 May 2018

Keywords

  • BRAF
  • CDK4
  • drug resistance
  • drug tolerance
  • melanoma

Cite this

Martin, C. A., Cullinane, C., Kirby, L., Abuhammad, S., Lelliott, E. J., Waldeck, K., ... Sheppard, K. E. (2018). Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance. International Journal of Cancer, 142(10), 2139-2152. https://doi.org/10.1002/ijc.31220
Martin, Claire A. ; Cullinane, Carleen ; Kirby, Laura ; Abuhammad, Shatha ; Lelliott, Emily J. ; Waldeck, Kelly ; Young, Richard J. ; Brajanovski, Natalie ; Cameron, Donald P. ; Walker, Rachael ; Sanij, Elaine ; Poortinga, Gretchen ; Hannan, Ross D. ; Pearson, Richard B. ; Hicks, Rodney J. ; McArthur, Grant A. ; Sheppard, Karen E. / Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance. In: International Journal of Cancer. 2018 ; Vol. 142, No. 10. pp. 2139-2152.
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title = "Palbociclib synergizes with BRAF and MEK inhibitors in treatment na{\"i}ve melanoma but not after the development of BRAF inhibitor resistance",
abstract = "Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment na{\"i}ve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug-tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors.",
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Martin, CA, Cullinane, C, Kirby, L, Abuhammad, S, Lelliott, EJ, Waldeck, K, Young, RJ, Brajanovski, N, Cameron, DP, Walker, R, Sanij, E, Poortinga, G, Hannan, RD, Pearson, RB, Hicks, RJ, McArthur, GA & Sheppard, KE 2018, 'Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance', International Journal of Cancer, vol. 142, no. 10, pp. 2139-2152. https://doi.org/10.1002/ijc.31220

Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance. / Martin, Claire A.; Cullinane, Carleen; Kirby, Laura; Abuhammad, Shatha; Lelliott, Emily J.; Waldeck, Kelly; Young, Richard J.; Brajanovski, Natalie; Cameron, Donald P.; Walker, Rachael; Sanij, Elaine; Poortinga, Gretchen; Hannan, Ross D.; Pearson, Richard B.; Hicks, Rodney J.; McArthur, Grant A.; Sheppard, Karen E.

In: International Journal of Cancer, Vol. 142, No. 10, 15.05.2018, p. 2139-2152.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance

AU - Martin, Claire A.

AU - Cullinane, Carleen

AU - Kirby, Laura

AU - Abuhammad, Shatha

AU - Lelliott, Emily J.

AU - Waldeck, Kelly

AU - Young, Richard J.

AU - Brajanovski, Natalie

AU - Cameron, Donald P.

AU - Walker, Rachael

AU - Sanij, Elaine

AU - Poortinga, Gretchen

AU - Hannan, Ross D.

AU - Pearson, Richard B.

AU - Hicks, Rodney J.

AU - McArthur, Grant A.

AU - Sheppard, Karen E.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug-tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors.

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KW - BRAF

KW - CDK4

KW - drug resistance

KW - drug tolerance

KW - melanoma

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