Research ArticleCancer

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

See allHide authors and affiliations

Science Translational Medicine  31 May 2017:
Vol. 9, Issue 392, eaal5148
DOI: 10.1126/scitranslmed.aal5148

No escape for KRAS mutant tumors

Alterations in one of the RAS proteins, such as KRAS, are among the most common oncogenic mutations and also among the most difficult to treat. RAS mutant tumors are usually resistant to PARP inhibitors, one of the newest classes of anticancer therapeutics, and many other chemotherapy types. However, Sun et al. have discovered that inhibition of MEK or ERK (proteins in the RAS pathway) can reverse PARP inhibitor resistance in KRAS mutant tumors. MEK and PARP inhibitors are clinically approved drugs that provide a readily translatable therapeutic combination, and the authors have demonstrated its effectiveness in mouse models of aggressive tumors such as ovarian and pancreatic cancer.


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.

View Full Text

Stay Connected to Science Translational Medicine