Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

Chaoyang Sun, Yong Fang, Jun Yin, Jian Chen, Zhenlin Ju, Dong Zhang, Xiaohua Chen, Christopher P. Vellano, Kang Jin Jeong, Patrick Kwok Shing Ng, Agda Karina B. Eterovic, Neil H. Bhola, Yiling Lu, Shannon N. Westin, Jennifer R. Grandis, Shiaw Yih Lin, Kenneth L. Scott, Guang Peng, Joan Brugge, Gordon Mills

Research output: Contribution to journalArticle

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Abstract

Mutant RAS has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor-induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.

Original languageEnglish (US)
Article numberaal5148
JournalScience Translational Medicine
Volume9
Issue number392
DOIs
StatePublished - May 31 2017
Externally publishedYes

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Adenosine Diphosphate Ribose
Mitogen-Activated Protein Kinase Kinases
Neoplasms
DNA Damage
Recombinational DNA Repair
Therapeutics
Poly Adenosine Diphosphate Ribose
Mutation
Mitogen-Activated Protein Kinases
Apoptosis

ASJC Scopus subject areas

  • Medicine(all)

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Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. / Sun, Chaoyang; Fang, Yong; Yin, Jun; Chen, Jian; Ju, Zhenlin; Zhang, Dong; Chen, Xiaohua; Vellano, Christopher P.; Jeong, Kang Jin; Ng, Patrick Kwok Shing; Eterovic, Agda Karina B.; Bhola, Neil H.; Lu, Yiling; Westin, Shannon N.; Grandis, Jennifer R.; Lin, Shiaw Yih; Scott, Kenneth L.; Peng, Guang; Brugge, Joan; Mills, Gordon.

In: Science Translational Medicine, Vol. 9, No. 392, aal5148, 31.05.2017.

Research output: Contribution to journalArticle

Sun, C, Fang, Y, Yin, J, Chen, J, Ju, Z, Zhang, D, Chen, X, Vellano, CP, Jeong, KJ, Ng, PKS, Eterovic, AKB, Bhola, NH, Lu, Y, Westin, SN, Grandis, JR, Lin, SY, Scott, KL, Peng, G, Brugge, J & Mills, G 2017, 'Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers', Science Translational Medicine, vol. 9, no. 392, aal5148. https://doi.org/10.1126/scitranslmed.aal5148
Sun, Chaoyang ; Fang, Yong ; Yin, Jun ; Chen, Jian ; Ju, Zhenlin ; Zhang, Dong ; Chen, Xiaohua ; Vellano, Christopher P. ; Jeong, Kang Jin ; Ng, Patrick Kwok Shing ; Eterovic, Agda Karina B. ; Bhola, Neil H. ; Lu, Yiling ; Westin, Shannon N. ; Grandis, Jennifer R. ; Lin, Shiaw Yih ; Scott, Kenneth L. ; Peng, Guang ; Brugge, Joan ; Mills, Gordon. / Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. In: Science Translational Medicine. 2017 ; Vol. 9, No. 392.
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abstract = "Mutant RAS has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor-induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.",
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AU - Grandis, Jennifer R.

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