A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer

Abstract

KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.

ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma

“…While KRAS is clearly a potent oncogenic driver, additional genomic aberrations may exist in KRAS-driven lung adenocarcinomas that could impact the therapeutic response. For instance, KRAS mutations were recently shown to cocluster with mutations affecting the p53 response in lung adenocarcinoma (6). These data suggest that an impaired DNA damage response maybe selected in KRASmutant lung adenocarcinoma.…”

“…Intratracheal administration of adenoviral Cre recombinase (Adeno-Cre) leads to the expression of oncogenic Kras G12D from its endogenous locus. In addition to this simple Kras-driven model, we also used Kras LSL.G12D/wt ; Tp53 fl/fl mice, in which both Tp53 alleles are flanked by LoxP sites (6,28,31). In these compound-mutant mice, Adeno-Cre drives expression of Kras G12D and simultaneous deletion of both Tp53 alleles.…”

“…These regimens have shown promising preclinical activity and multiple clinical trials are underway, but the clinical feasibility and validity has yet to be demonstrated. In addition, combined inhibition of the checkpoint kinases CHK1 and MK2 was recently shown to display preclinical activity against different Kras-driven cancer entities (6).…”

“…Two pieces of circumstantial evidence may support this hypothesis. First, it was recently shown that acute expression of oncogenic Kras causes DNA damage, likely due to the induction of replicative stress (6,50). Second, it was also shown that murine embryonic fibroblasts that were engineered to lack both Tp53 and Atm display a substantially enhanced sensitivity against genotoxic chemotherapeutics, such as the topoisomerase I poisons camptothecin and topotecan, the topoisomerase II poisons doxorubicin, epirubicin and etoposide, as well as the antimetabolites 5-fluorouracil and gemcitabine, but not to cisplatin, carboplatin, and oxaliplatin, and the taxanes, docetaxel and paclitaxel (51).…”

Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer

“…Interestingly, both SMYD2 (Xu et al 2015) and MAPKAPK3 (Wysk et al 1999) have been linked to IL-6 and TNFα regulation. MAPKAPK3 and its closely related family member, MAPKAPK2 (which is not methylated by SMYD2), have also been implicated in DNA damage response and chemotherapy response (Morandell et al 2013;Dietlein et al 2015), and their common substrate, HSP27, has been shown to mediate the effects of gemcitabine toxicity in PDAC cells (Mori-Iwamoto et al 2007;Kuramitsu et al 2012). These observations and our data showing greater effects of chemotherapy upon inhibition of SMYD2 in PDAC cells raise the possibility that SMYD2 inhibitors and MAPKAPK2/3 inhibitors may be used in combination to enhance the effects of chemotherapy in PDAC patients.…”