CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours

Abstract

Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation.

Associating transcriptional modules with colon cancer survival through weighted gene co-expression network analysis

“…Therefore, KRAS may affect cell cycle processes. In a recent study, CDK1 is reported as a synthetic lethality target for KRAS mutation in colon cancer [34]. Our study highlisht RAD51AP1 as a prognostic marker and therapeutic target.…”

Cell cycle proteins as promising targets in cancer therapy

“…Inhibitors that selectively inhibit CDK4 but not CDK6 (and vice versa) may also be developed, and they could possibly reduce the adverse effects without compromising the therapeutic benefit. Furthermore, CDK2- and CDK1-selective inhibitors will likely be developed, as they may have clinical utility for specific cancer subtypes 55, 66–68 …”

“…CDK1 was shown to be required for tumour formation and progression. For example, liver-specific ablation of Cdk1 conferred resistance to NRAS G12V -induced liver tumorigenesis 65 , while CDK1 inhibition blocked the growth of KRAS -mutant (G12V, G12D or G12S) colorectal cancer xenografts 66 . However, CDK1 activity is essential for proliferation also in normal, non-transformed cells 59 , arguing against inhibition of CDK1 as a viable therapeutic strategy.…”

Integration of pathway, cellular and genetic context reveals principles of synthetic lethality that affect reproducibility

“…Since our network analysis highlighted shared pathways and complexes across studies, we hypothesized that Network SL genes may represent synthetic lethals that are more robust, and hence more likely to be reproduced in follow up studies. To address this we asked if they were more likely to be recovered in a series of more recent RNAi screens that were not used for network identification as compared to 26 previously published KRAS synthetic lethal genes curated from the literature (Literature SL) (Table 2B) (Costa-Cabral et al, 2016;Kim et al, 2013Kim et al, , 2016. Both Kim et al 2013(Kim et al, 2013 and Kim et al 2016(Kim et al, 2016 studies used panels of KRAS mutant versus wild-type lung cancer lines, and the Costa-Cabral study (Costa-Cabral et al, 2016) used an isogenic panel of colorectal cancer lines.…”

“…It is as yet undruggable, activates a variety of signaling pathways, and is exemplary to the challenges in identifying synthetic lethals. While a multitude of studies have sought to define KRAS synthetic lethal genes (Costa-Cabral et al, 2016;Kim et al, 2013Kim et al, , 2016Luo et al, 2009;Scholl et al, 2009;Steckel et al, 2012), they have been notable for the fact that they hardly overlap, which has been attributed to the use of different cell lines and screening libraries that may suffer from off-target effects and partial knockdowns (Downward, 2015). As a result, many of the published synthetic lethal genes that have been explored independently have failed to reproduce (Fröhling and Scholl, 2011;Tessema et al, 2014).…”