Reference Detail

Ref Type

Journal Article

PMID

(26140595)

Authors

Dietlein F, Kalb B, Jokic M, Noll EM, Strong A, Tharun L, Ozretić L, Künstlinger H, Kambartel K, Randerath WJ, Jüngst C, Schmitt A, Torgovnick A, Richters A, Rauh D, Siedek F, Persigehl T, Mauch C, Bartkova J, Bradley A, Sprick MR, Trumpp A, Rad R, Saur D, Bartek J, Wolf J, Büttner R, Thomas RK, Reinhardt HC

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell	162	1	2015 Jul 02	146-59	Cell

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PF3644022	PF3644022	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PF3644022		PF-3644022		PF3644022 is an ATP-competitive MAPK-activated protein kinase-2 (MK2) inhibitor that induces apoptosis in tumor cells (PMID: 26140595).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	Advanced Solid Tumor	predicted - sensitive	PF-00477736 + PF3644022	Preclinical - Cell culture	Actionable	In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of transformed cells over expressing BRAF V600E in culture, while single agent inhibition had no effect (PMID: 26140595).	26140595
BRAF mutant	colon cancer	predicted - sensitive	PF-00477736 + PF3644022	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of BRAF mutant colon cancer (PMID: 26140595).	26140595
BRAF mutant	Advanced Solid Tumor	predicted - sensitive	PF-00477736 + PF3644022	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of various cancer cell lines harboring BRAF mutations in culture and in cell line xenograft models (PMID: 26140595).	26140595
CDKN2A loss	Advanced Solid Tumor	predicted - sensitive	PF-00477736 + PF3644022	Preclinical - Cell culture	Actionable	In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited growth of multiple cancer cell lines harboring CDKN2A loss and in Cdkn2a-depleted transformed cells in culture (PMID: 26140595).	26140595
CDKN2A del	lung cancer	predicted - sensitive	PF-00477736 + PF3644022	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 synergistically inhibited tumor growth in cell line xenograft models of CDKN2A-deleted lung cancer (PMID: 26140595).	26140595
BRAF N581S	lung adenocarcinoma	predicted - sensitive	PF-00477736 + PF3644022	Preclinical - Patient cell culture	Actionable	In a preclinical study, Chk1 inhibitor PF-477736 and MK2 inhibitor PF3644022 combination treatment resulted in significant apoptosis in primary tumor cells isolated from a lung adenocarcinoma patient harboring BRAF N581S in culture (PMID: 26140595).	26140595