Identification of cancer-related genes by KRAS phylogenetics

Identification of cancer-‐related genes by KRAS phylogenetics

Joshua Elkington1 1Department of Molecular and Cellular Biology, Harvard University Cambridge, MA 02138 double spaced

The hundreds of eukaryotic genomes now sequenced allow the tracking of the evolution of human genes, and the analysis of patterns of their conservation across eukaryotic clades.

Phylogenetic profiling describes the relative sequence conservation or divergence of orthologous proteins across a set of reference genomes.

Proteins that functionally interact in common pathways or in protein complexes can show similar patterns of relaxation of conservation in phylogenetic clades that no longer require that complex, pathway, or function, or conversely show similar levels of relative conservation in organisms that continue to utilize those functions. Phylogenetic profiling has been used to predict gene functions (Eisen and Wu, 2002; Enault et al, 2004; Jiang, 2008), protein–protein interactions (Sun et al, 2005; Kim and Subramaniam, 2006), protein subcellular location (Marcotte et al, 2000; Pagliarini et al, 2008), cellular organelle location (Avidor-‐Reiss et al, 2004; Hodges et al, 2012), and gene annotation (Merchant et al, 2007).

A number of improvements to phylogenetic profiling have increased its sensitivity and selectivity (Ruano-‐Rubio et al, 2009; Pellegrini, 2012).

A modified phylogenetic profiling method that uses a continuous measure of relative conservation in each species revealed many new components of the Caenorhabditis elegans RNAi machinery (Tabach et al, 2013).

Proteins with similar patterns of conservation or divergence across different organisms are more likely to act in the same pathways5. To identify proteins that share an evolutionary history with validated small RNA pathway proteins, we determined the phylogenetic profiles of approximately 20,000 C. elegans proteins in 85 genomes, representing diverse taxa of the eukaryotic tree of life: 33 animals, 6 land plants, 1 alga, 31 Ascomycota fungi, 3 Basidiomycota fungi and 12 protists. Of the ~20,000 C. elegans proteins, 10,054 show homologues in non-‐nematode

eukaryotic genomes (Supplementary Table 1). Following correlation and clustering, this analysis sorts genes into clades of conservation and relative divergence or loss in the various organisms as suites of genes are maintained from common ancestors or diverge in particular lineages6. Protein divergence or loss in particular taxonomic clades is not random; entire suites of proteins can diverge or be lost as particular taxa specialize and no longer require ancestral functions. The correlated loss of proteins has been used to assign roles for nuclear-‐encoded mitochondrial proteins7 and eukaryotic cilia-‐associated proteins8.

We developed a non-‐binary method of phylogenetic profiling to cluster all protein sequences encoded by C. elegans genes. BLAST scores were normalized to the length of the query sequence and for relative phylogenetic distance between C. elegans and the queried organism9. The matrix of 864,644 conservation scores for the 10,054 C. elegans proteins in the 86 genomes was queried either with a single protein to generate a ranking of other C. elegans proteins with the most similar pattern of conservation values or using a more global hierarchical clustering method (Fig. 1a). Proteins of the same families exhibit similar patterns of phylogenetic conservation and therefore tend to group together in the hierarchical clustering. However, many phylogenetic clusters include proteins with no sequence similarity; only their conservation or divergence in genomes is correlated. The ability of this non-‐binary method of phylogenetic profiling to cluster proteins based on function is exemplified by the clustering of proteins known to act as members of complexes. For example, the known protein components of the sensory cilium have highly correlated phylogenetic profiles characterized by loss in particular vertebrates and all fungi and plants and retention in particular protists, whereas the extraordinarily high and universal conservation of ribosomal and translation factor proteins clusters many of these translation components (Supplementary Fig. 1a, b).

GTPase KRas also known as V-‐Ki-‐ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene.[1][2]

The protein product of the normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.[3] Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS is usually tethered to cell membranes because of the presence of an isoprenyl group on its C-‐terminus.

1. McGrath JP, Capon DJ, Smith DH, Chen EY, Seeburg PH, Goeddel DV, Levinson AD (1983). "Structure and organization of the human Ki-‐ras proto-‐oncogene and a related processed pseudogene". Nature 304 (5926): 501–6. doi:10.1038/304501a0. PMID 6308466.

2. Jump up ^ Popescu NC, Amsbaugh SC, DiPaolo JA, Tronick SR, Aaronson SA, Swan DC (March 1985). "Chromosomal localization of three human ras genes by in situ molecular hybridization". Somat. Cell Mol. Genet. 11 (2): 149–55.

doi:10.1007/BF01534703. PMID 3856955. 3. Kranenburg O (November 2005). "The KRAS oncogene: past, present, and

future". Biochim. Biophys. Acta 1756 (2): 81–2. doi:10.1016/j.bbcan.2005.10.001. PMID 16269215.

Although activating KRAS mutations occur frequently in cancer, targeting this oncogene has proved difficult. Three groups have now identified pathways that have not been previously linked to KRAS — all of which may provide pharmacologically tractable anticancer targets — and that are crucial in cancer cells dependent on activated KRAS.

Steve Elledge and colleagues conducted a genome-‐wide RNA interference (RNAi) screen in an isogenic pair of DLD-‐1 colorectal cancer cell lines: one that carried an endogenous activated KRAS allele (KRASWT/G13D cells) and one in which this allele was disrupted (KRASWT/− cells). By finding short hairpin RNAs (shRNAs) that were selectively depleted over time in KRASWT/G13D cells compared with KRASWT/− cells, and refining their initial list using a second isogenic pair of HCT116 colorectal cancer cells, they identified a functionally diverse list of 50 genes that might have synthetic lethal interactions with activated KRAS. This list included many genes involved in mitotic regulation, such as Polo-‐like kinase 1 (PLK1) and genes that encode anaphase-‐promoting complex/cyclosome (APC/C) subunits. Cells expressing KRASG13D were sensitive to PLK1 inhibition in vitro and in mouse xenograft models. The cells were also sensitive to inhibition of the ubiquitin ligase APC/C in vitro. As APC/C ultimately requires proteasome activity, the authors showed that the proteasome inhibitors MG132 and bortezomib were synthetic lethal with activated KRAS. Furthermore, non-‐small-‐cell lung cancer (NSCLC) cell lines were more sensitive to APC/C subunit knockdown if they harboured Ras mutations. Is this pathway relevant in vivo? Analysis of Ras-‐associated gene signatures in human lung tumour samples indicated that those tumours with a positive Ras signature that also had a signature suggestive of decreased APC/C activity correlated with increased patient survival.

Gary Gilliland, Bill Hahn and colleagues performed a similar RNAi screen across eight cancer cell lines (four that expressed a KRAS mutant and four that were KRAS wild type) and found that shRNAs targeting the kinase STK3 3 impaired cell viability and proliferation only in cells that were dependent on mutant KRAS. This was confirmed in several other cell types (25 in total), including both haematopoietic and epithelial cancer cell lines, and STK33 shRNA reduced tumour formation by 4 different KRAS-‐dependent epithelial cancer cell lines in immunocompromised mice. Interestingly, DLD-‐1 cells, as used in the studies above, were also sensitive to STK33 knockdown. Forcing KRAS dependence by expressing KRASG13D in two KRAS-‐independent acute myeloid leukaemia cell lines also led to sensitivity to STK33. What does STK33 do? The authors examined the activation of several signalling

pathways in cells with STK33 suppression. Loss of STK33 decreased phosphorylation and activity of the S6K1 kinase and downstream phosphorylation of the proapoptotic BH3-‐only protein BAD, leading to apoptosis.

Jeff Settleman and colleagues examined the effect of KRAS depletion in several lung and pancreatic cancer cell lines. By comparing KRAS-‐dependent cells (in which KRAS knockdown induced apoptosis) with KRAS-‐independent cells, they noted that KRAS-‐dependent cells tended to have an epithelial morphology, whereas KRAS-‐independent cells appeared to be more mesenchymal. Induction of an epithelial–mesenchymal transition (EMT) in KRAS-‐dependent H358 NSCLC cells allowed these cells to become KRAS independent, and conversely, reversal of EMT in KRAS-‐independent cells rendered these cells KRAS dependent. The authors then derived a gene expression signature of KRAS dependency, which was also associated with well-‐differentiated primary lung tumours. From this signature, they found three pharmacologically tractable targets that were upregulated in KRAS-‐dependent cells: the kinase SYK, the RON receptor tyrosine kinase (encoded by MST1R) and β6 integrin (encoded by ITGB6). shRNAs against SYK and ITGB6 led to EMT and apoptosis in two KRAS-‐dependent cell lines, but not two KRAS-‐independent cell lines, whereas MST1R knockdown was context specific, inducing apoptosis in only one KRAS-‐dependent cell line. KRAS-‐dependent cells were also more sensitive to a pharmacological SYK inhibitor.

References and links

ORIGINAL RESEARCH PAPER Luo, J. et al. A genome-‐wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009) Article PubMed

Scholl, C. et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137, 821–833 (2009)

Article PubMed

Singh, A. et al. A gene expression signature associated with "K-‐Ras addiction" reveals regulators of EMT and tumor cell survival. Cancer Cell 15, 489–500 (2009)

Article PubMed

The RAS (rat sarcoma) protein family members are all low-‐molecular-‐weight GTP-‐binding proteins that play a role in regulating cell differentiation, proliferation, and survival.(1, 2) There are three main members of the RAS family: HRAS, NRAS, and KRAS, all of which have been found to drive cancer formation and progression.(1-‐3) Mutations in RAS are found in approximately 30% of human cancers.(2) In the

absence of a RAS mutation, increased RAS activity in human tumors has been shown to be the result of gene amplification, overexpression, or increased upstream activation.(4) Single point mutations of the RAS gene, affecting residues G12 and G13, abolish GAP-‐induced GTP hydrolysis through steric hindrance, while mutations of residue Q61 interfere with the coordination of a water molecule necessary for GTP hydrolysis.(5) These mutations render the protein constitutively active, and the persistence of active GTP-‐bound RAS leads to the constant activation of its downstream effector pathways. KRAS is the most frequently mutated RAS isoform, having been shown to be mutated in 90% of pancreatic adenocarcinomas, 45% of colorectal cancers, and 35% of lung adenocarcinomas.(2, 6) KRAS mutations have been associated with increased tumorigenicity and poor prognosis.(4) Additionally, the inhibition of activated RAS has been shown to revert malignant cells to a nonmalignant phenotype and cause tumor regression both in vitro and in vivo.(4, 7, 8) Thus, KRAS is an attractive therapeutic target for a number of cancers. While the development of a small molecule inhibitor of the constitutively active KRAS protein would be ideal as a cancer therapeutic, 25 years of work on drugs targeting the GTP binding pocket of mutant KRAS have thus far proven to be unsuccessful. To date, no effective therapy that specifically targets mutant KRAS is available. Targeting the constitutively active molecular switch of KRAS is quite difficult because the role of GDP or GTP is to stabilize inactive or active states of the RAS protein.(9) This is in contrast to protein kinases in which phosphoryl transfer from ATP to a substrate is a rapid, catalytic process.(9) Additionally, because of picomolar affinity between KRAS and GTP, as well as the micromolar concentration of GTP in the cell, a competitive inhibitor is not particularly feasible.(9) Furthermore, KRAS activation and signaling are accomplished through protein–protein interactions (PPIs) with guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and the various KRAS effector proteins.(10) PPIs are challenging to target because of the relatively featureless topologies of the surfaces involved.(11) In spite of these issues, a number of attempts have been made to target aberrant KRAS signaling at different levels.

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Abstract

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present the problem his or her research addresses why this problem is significant how it applies to the larger field of research if the manuscript is novel or creative in some way, it should be clearly stated. The author should address relevant studies by other researchers; however, a full history of the topic is not needed Finally, the author must clearly state the hypothesis and briefly summarize the methods used to investigate that hypothesis. The Introduction should contain all the background information a reader needs to

understand the rest of the author’s paper. This means that all important concepts should be defined Methods and Materials

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In this section, the author should thoroughly detail the results of the experiments, models, or theories developed in the research The results should be supplemented by figures and tables, which should be briefly explained. Discussion and Conclusions

The design of a successful cancer therapeutic relies on an understanding of the biology underlying the disease. The idea that cells signal in a linear fashion is quickly becoming antiquated and is being replaced with circuit-‐type models. Likewise, cancer treatments need to be designed under the notion of circuit signaling. We expect that employing this rationale will lead to better treatments, more effective drug combinations, and better outcomes for patients. In this section, the author should restate the problem he or she was attempting to address and summarize how the results have addressed it The author should discuss the significance of all the results and interpret their meaning Potential sources of error should be discussed Finally, the author should tie his or her conclusions into the “big picture” by suggesting the implications and applications this research might have The author should discuss how this research affects the field, what it adds to existing research what future experiments could be carried out.

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The RAS proteins play a role in cell differentiation, proliferation, and survival. Aberrant RAS signaling has been found to play a role in 30% of all cancers. KRAS, a key member of the RAS protein family, is an attractive cancer target, as frequent point mutations in the KRAS gene render the protein constitutively active. A number of attempts have been made to target aberrant KRAS signaling by identifying small molecule compounds that (1) are synthetic lethal to mutant KRAS, (2) block KRAS/GEF interactions, (3) inhibit downstream KRAS effectors, or (4) inhibit the post-‐translational processing of RAS proteins. In addition, inhibition of novel targets outside the main KRAS signaling pathway, specifically the cell cycle related kinase

PLK1, has been shown have an effect in cells that harbor mutant KRAS. Herein we review the use of various high-‐throughput screening assays utilized to identify new small-‐molecule compounds capable of targeting mutant KRAS-‐driven cancers.

Figure 3. Downstream signaling of RAS. Ras interacts with a number of downstream effectors. The main ones include RAF protein kinases, phosphoinositide 3-‐kinases (PI3Ks), guanine nucleotide exchange factors for the RAS-‐related protein Ral (RalGDS), and phospholipase Cε (PLCε).

gene orienteer

Symbol Description Description2

KRAS

v-‐Ki-‐ras2 Kirsten rat sarcoma viral oncogene homolog [Source:HGNC Symbol;Acc:6407] RAS PRECURSOR

NRAS

neuroblastoma RAS viral (v-‐ras) oncogene homolog [Source:HGNC Symbol;Acc:7989] RAS PRECURSOR

HRAS

v-‐Ha-‐ras Harvey rat sarcoma viral oncogene homolog [Source:HGNC Symbol;Acc:5173] RAS PRECURSOR

RAP2A

RAP2A, member of RAS oncogene family [Source:HGNC Symbol;Acc:9861] RAS RELATED RAP PRECURSOR

RAP1A RAP1A, member of RAS RAS RELATED RAP PRECURSOR

oncogene family [Source:HGNC Symbol;Acc:9855]

RAP1B

RAP1B, member of RAS oncogene family [Source:HGNC Symbol;Acc:9857] RAS RELATED RAP PRECURSOR

RRAS

related RAS viral (r-‐ras) oncogene homolog [Source:HGNC Symbol;Acc:10447] RAS PRECURSOR

RAP2B

RAP2B, member of RAS oncogene family [Source:HGNC Symbol;Acc:9862] RAS RELATED RAP PRECURSOR

RAP2C

RAP2C, member of RAS oncogene family [Source:HGNC Symbol;Acc:21165] RAS RELATED RAP PRECURSOR

RRAS2

related RAS viral (r-‐ras) oncogene homolog 2 [Source:HGNC Symbol;Acc:17271] RAS PRECURSOR

MAP2K6

mitogen-‐activated protein kinase kinase 6 [Source:HGNC Symbol;Acc:6846]

DUAL SPECIFICITY MITOGEN ACTIVATED KINASE KINASE MAP KINASE KINASE MAPKK EC_2.7.12.2 MAPK/ERK KINASE MEK

RALA

v-‐ral simian leukemia viral oncogene homolog A (ras related) [Source:HGNC Symbol;Acc:9839] RAS RELATED PRECURSOR

DDX19A

DEAD (Asp-‐Glu-‐Ala-‐As) box polypeptide 19A [Source:HGNC Symbol;Acc:25628]

ATP DEPENDENT RNA HELICASE EC_3.6.4.13

MRAS

muscle RAS oncogene homolog [Source:HGNC Symbol;Acc:7227]

RAS RELATED M RAS PRECURSOR RAS RELATED R RAS3

DDX19B

DEAD (Asp-‐Glu-‐Ala-‐As) box polypeptide 19B [Source:HGNC Symbol;Acc:2742]


RIT2

Ras-‐like without CAAX 2 [Source:HGNC Symbol;Acc:10017]

GTP BINDING RIT1 RAS EXPRESSED IN MANY TISSUES RAS WITHOUT CAAX 1

RHOD

ras homolog gene family, member D [Source:HGNC Symbol;Acc:670] RHO RELATED GTP BINDING PRECURSOR

DDX25

DEAD (Asp-‐Glu-‐Ala-‐Asp) box polypeptide 25 [Source:HGNC Symbol;Acc:18698]


RND2

Rho family GTPase 2 [Source:HGNC Symbol;Acc:18315]

RHO RELATED GTP BINDING PRECURSOR RHO FAMILY GTPASE

SGK2

serum/glucocorticoid regulated kinase 2 [Source:HGNC Symbol;Acc:13900]

SERINE/THREONINE KINASE EC_2.7.11.1 SERUM/GLUCOCORTICOID REGULATED KINASE

PKN3

protein kinase N3 [Source:HGNC Symbol;Acc:17999]

SERINE/THREONINE KINASE EC_2.7.11.13 KINASE C KINASE C RELATED KINASE

ACTR2

ARP2 actin-‐related protein 2 homolog (yeast) [Source:HGNC Symbol;Acc:169] ACTIN RELATED 2 ACTIN 2

YWHAH

tyrosine 3-‐monooxygenase/tryptophan 5-‐monooxygenase activation protein, eta polypeptide [Source:HGNC Symbol;Acc:12853] UNKNOWN

RALB

v-‐ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein) [Source:HGNC Symbol;Acc:9840] RAS RELATED PRECURSOR

MAP2K3

mitogen-‐activated protein kinase kinase 3 [Source:HGNC Symbol;Acc:6843]

DUAL SPECIFICITY MITOGEN ACTIVATED KINASE KINASE MAP KINASE KINASE MAPKK EC_2.7.12.2 MAPK/ERK KINASE MEK

SGK1

serum/glucocorticoid regulated kinase 1 [Source:HGNC Symbol;Acc:10810]

SERINE/THREONINE KINASE EC_2.7.11.1 SERUM/GLUCOCORTICOID REGULATED KINASE

VPS4B

vacuolar protein sorting 4 homolog B (S. cerevisiae) VACUOLAR SORTING ASSOCIATED

[Source:HGNC Symbol;Acc:10895]

YWHAZ

tyrosine 3-‐monooxygenase/tryptophan 5-‐monooxygenase activation protein, zeta polypeptide [Source:HGNC Symbol;Acc:12855] UNKNOWN

PRKCQ

protein kinase C, theta [Source:HGNC Symbol;Acc:9410] KINASE C TYPE EC_2.7.11.13 NPKC

YWHAG

tyrosine 3-‐monooxygenase/tryptophan 5-‐monooxygenase activation protein, gamma polypeptide [Source:HGNC Symbol;Acc:12852] UNKNOWN

MAPK14

mitogen-‐activated protein kinase 14 [Source:HGNC Symbol;Acc:6876]

MITOGEN ACTIVATED KINASE MAP KINASE EC_2.7.11.24

RHOA

ras homolog gene family, member A [Source:HGNC Symbol;Acc:667] GTP BINDING PRECURSOR

RIT1

Ras-‐like without CAAX 1 [Source:HGNC Symbol;Acc:10023]

GTP BINDING RIT1 RAS EXPRESSED IN MANY TISSUES RAS WITHOUT CAAX 1

AC034102.1

RAS RELATED RAB

DIRAS1

DIRAS family, GTP-‐binding RAS-‐like 1 [Source:HGNC Symbol;Acc:19127]

GTP BINDING DI DISTINCT SUBGROUP OF THE RAS FAMILY MEMBER

ARF3

ADP-‐ribosylation factor 3 [Source:HGNC Symbol;Acc:654] ADP RIBOSYLATION FACTOR

YWHAB

tyrosine 3-‐monooxygenase/tryptophan 5-‐monooxygenase activation protein, beta polypeptide [Source:HGNC Symbol;Acc:12849] UNKNOWN

ARF5


CTDSP1

CTD (carboxy-‐terminal domain, RNA polymerase II, polypeptide A) small phosphatase 1 [Source:HGNC Symbol;Acc:21614]

CARBOXY TERMINAL DOMAIN RNA POLYMERASE II POLYPEPTIDE A SMALL PHOSPHATASE SMALL C TERMINAL DOMAIN PHOSPHATASE SMALL CTD PHOSPHATASE NUCLEAR LIM INTERACTOR INTERACTING FACTOR NLI INTERACTING FACTOR

PAK1

p21 protein (Cdc42/Rac)-‐activated kinase 1 [Source:HGNC Symbol;Acc:8590]

SERINE/THREONINE KINASE PAK EC_2.7.11.1 P21 ACTIVATED KINASE PAK PAK PAK

ARF4


ARF1


RHEBL1

Ras homolog enriched in brain like 1 [Source:HGNC Symbol;Acc:21166]

GTPASE RHEBL1 PRECURSOR RAS HOMOLOG ENRICHED IN BRAIN 1 RHEB 1

PPP3CB

protein phosphatase 3, catalytic subunit, beta isozyme [Source:HGNC Symbol;Acc:9315]

SERINE/THREONINE PHOSPHATASE 2B CATALYTIC SUBUNIT EC_3.1.3.16 CALMODULIN DEPENDENT CALCINEURIN A SUBUNIT CAM PRP CATALYTIC SUBUNIT

VPS4A

vacuolar protein sorting 4 homolog A (S. cerevisiae) [Source:HGNC Symbol;Acc:13488] VACUOLAR SORTING ASSOCIATED

RAB8B

RAB8B, member RAS oncogene family [Source:HGNC Symbol;Acc:30273] RAS RELATED RAB

STK38L

serine/threonine kinase 38 like [Source:HGNC Symbol;Acc:17848] SERINE/THREONINE KINASE EC_2.7.11.1

RAB8A

RAB8A, member RAS oncogene family [Source:HGNC Symbol;Acc:7007] RAS RELATED RAB

MAPK13 mitogen-‐activated protein kinase 13

MITOGEN ACTIVATED KINASE MAP KINASE EC_2.7.11.24

[Source:HGNC Symbol;Acc:6875]

MAPK3

mitogen-‐activated protein kinase 3 [Source:HGNC Symbol;Acc:6877]

MITOGEN ACTIVATED KINASE MAP KINASE MAPK EC_2.7.11.24 EXTRACELLULAR SIGNAL REGULATED KINASE ERK

Identification of cancer-related genes by KRAS phylogenetics

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