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Bobby Hodges, Elizabeth Ross, Natalie Simak , Keith Solvang and Eliot Vildaver. Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants. Diseased Genome Hospital. http:// blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg.

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Bobby hodges elizabeth ross natalie simak keith solvang and eliot vildaver

Bobby Hodges, Elizabeth Ross, Natalie Simak, Keith Solvang and Eliot Vildaver

Lung Cancer: The Breathtaking Battle of TKIs and EGFR Mutants


Diseased

Genome

Hospital

http://blogs.usask.ca/medical_education/archive/ElksRehabFront%2520Door.jpg


http://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpghttp://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpg


http://img.quamut.com/chart/9471/02_healthy_sick_x-ray.jpghttp://1.bp.blogspot.com/_HI2mCx5P3H0/SLlEQoHj8AI/AAAAAAAAA8Q/My7tf78TNc8/s320/hospital-bed-786282.jpg


http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=yhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y


Where are we headed
Where Are We Headed?http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

http://www.freefoto.com/images/21/16/21_16_2---Single-Carriageway-Road_web.jpg


Cancer
Cancerhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

http://www.odec.ca/projects/2005/thog5n0/public_html/Tumour.gif


History of lung cancer
History of Lung Cancerhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

http://www.icowman.com/uploadfiles/2007072409225175.jpg

http://www.icowman.com/uploadfiles/2007072409225175.jpg


Pathology
Pathologyhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

Non Small Cell

Small Cell

Bronchi

Grows rapidly

Spreads quickly

  • Squamous cell carcinoma

  • Adenocarcinoma

  • Large-cell carcinoma

http://images.google.com/imgres?imgurl=http://upload.wikimedia.org/

Lynch et al., (2004)

http://images.google.com/imgres?imgurl=http://www.dkimages.com/discover/previews/852/20223038.JPG


Risk factors
Risk Factorshttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg


You are not alone
You Are Not Alonehttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

  • This year approximately 200,000 people will be diagnosed with lung cancer

  • NSCLC accounts for 80% of all lung cancers

http://www.cdc.gov/cancer/lung/statistics/

http://seo2.0.onreact.com/wp-content/uploads/2008/09/you-re-not-alone.jpg


Epidemiology
Epidemiologyhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

http://medicineworld.org/cancer/lung/

http://images.google.com/


What next
What Next?http://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

While there is no known cure as of right now, there ARE options!

Imatinib

Gefinitib

Cisplatin

http://dspace.mit.edu

http://dspace.mit.edu


EGFhttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

ERBB2

Cisplatin

Imatinib

Protein

Cascade

Gefitinib

EGFR

P

?

Nucleus

?


Phttp://www.cardiothoracicsurgery.org/content/2/1/16/figure/F1?highres=y

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus


Implications of chromosomal loci in the development of lung cancer
Implications of Chromosomal Loci in the Development of Lung Cancer

http://academic.evergreen.edu

http://rosenblumtv.files.wordpress.com

http://www.pharmgkb.org


Chromosomes
Chromosomes Cancer

  • Compact structures of DNA

  • Contains thousands of genes

Chromatid

Centromere

Genes

http://staff.jccc.net/PDECELL/celldivision/chromosome1.gif


Single nucleotide polymorphisms snps
Single Nucleotide Polymorphisms (SNPs) Cancer

  • Single variation in nucleotide base pairs

  • Alleles are a result of SNPs within gene sequence

  • SNP’s are the basis for lung cancer susceptibility

http://www.dnalandmarks.com/english/pictures/what_are_snps.jpg


Genome wide association studies
Genome-wide Association Studies Cancer

  • Variation across genomes

  • Genotype cases along with controls

  • Find roles that genes play in disease

  • Large sample sizes

http://www.blog.speculist.com/archives/dna2two


Identify ing regions on chromosomes
Identify Cancering Regions On Chromosomes

6 Regions Away

p-arm

Centromere

Region 5q6

q-arm

5

http://images.google.com/


Three regions of association
Three CancerRegions of Association

http://upload.wikimedia.org/

http://upload.wikimedia.org/


Nicotinic acetylcholine receptor genes found on 15q24 and 15q25
Nicotinic Acetylcholine Receptor Genes Found on 15q24 and 15q25

http://www.jyi.org/articleimages/88/originals/img0.jpg

Nicotine binds and stimulates acetylcholine ion channel-linked in neurons


How were these regions discovered
How were these regions discovered? 15q25

(Hung et al., 2008)


15q24 highly linked with smoking behavior
15q24 highly linked with smoking behavior 15q25

(Thorgeirson et al., 2008)


Tert gene found on 5p15 33
TERT gene found on 5p15.33 15q25

Cancerous Growth

http://images.google.com/i


5p15 33 shows similar results
5p15.33 shows similar results 15q25

(McKay et al., 2008)


P 15q25

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus



Egfr erbb2 forms a heterodimer
EGFR/ERBB2 Forms a 15q25Heterodimer

EGFR

EGFR

EGF

EGFR

ERBB2

ERBB2

P

P

Proliferation

Protein

Cascade

Survival

Nucleus

Apoptosis



Mutated egfr leads to cancer
Mutated EGFR Leads to Cancer 15q25

ERBB2

EGFR

P

Protein

Cascade

Proliferation

Nucleus


Mutated egfrs have distinct patterns of tyr phosphorylation
Mutated EGFRs have Distinct Patterns of Tyr 15q25Phosphorylation

(Chen et al., 2006)


Tyrosine kinase inhibitors tkis gefitinib
Tyrosine Kinase Inhibitors (TKIs) 15q25Gefitinib

EGFR

Tyrosine

Kinase

domain

ATP

TKI

ATP binding cleft on the kinase


Gefitinib suppresses phosphorylation of most egfr mutants
Gefitinib 15q25 Suppresses Phosphorylation of Most EGFR Mutants

(Chen et al., 2006)



Effectiveness of gefitinib is dependent on concentration
Effectiveness of 15q25Gefitinib is Dependent on Concentration

(Pedersen et al., 2005)


High doses of gefitinib decreases proliferation of mutated egfr cells
High Doses of 15q25Gefitinib Decreases Proliferation of Mutated EGFR Cells

(Pedersen et al., 2005)


Gefitinib has variable growth inhibitory effects
Gefitinib 15q25 has Variable Growth-Inhibitory Effects

(Chen et al., 2006)


P 15q25

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus


What Are the Roles of Proteins Associated with Lung Cancer? 15q25

http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg


Recap 15q25

Alanine

N-terminus

Tyrosine

P

P

C-terminus

P

Nucleus

Threonine

Leucine

Serine

Lysine



Domain attraction
Domain Attraction 15q25

ERBB2

P

P

PI3K

Protein Cascade

SH2

Change in Gene Expression

Nucleus



Main contributors to nsclc
Main Contributors to NSCLC 15q25

(Rikova et al. 2007)


Link between concentration and interaction
Link between Concentration and Interaction 15q25

(Jones et al. 2006)

Green andBlue circles =

Proteins involved in cascade

Interactions

Red lines =

Red circles =

EGFR Receptor


Other erbb2 associations
Other ERBB2 Associations 15q25

No. protein receptors

No. protein receptors

No. protein receptors

Affinity Threshold (nM) Affinity Threshold (nM) Affinity Threshold (nM)

(Jones et al. 2006)


Are there other types of proteins
Are there other types of Proteins? 15q25

http://en.wikipedia.org/wiki/Proteins


Other contributors to nsclc
Other Contributors to NSCLC 15q25

(Rikova et al. 2007)


Specifically some proteins more than others
Specifically, some proteins more than others 15q25

Amount of overphosphorylated protein in samples

Chart configured from Table1 of Rikova et al. 2007


Previous research amplification of met
Previous Research, Amplification of MET 15q25

(Engelman et al., 2007)


P 15q25

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus


What is the role of angiogenesis in lung cancer
What is the Role of Angiogenesis in Lung Cancer? 15q25

http://www.taconichills.k12.ny.us/webquests/noncomdisease/lungcancerpic.jpg


Angiogenesis and vegf
Angiogenesis and VEGF 15q25

http://www.researchvegf.com/researchvegf/multimedia/index.m#type-slides


Tumor angiogenesis is unregulated
Tumor Angiogenesis Is Unregulated 15q25

PDGF-β

VEGF-A

PDGFR-β

VEGFR

Tumors

Angiogenesis


Pi3k akt pathway in lung cancer
PI3K / 15q25Akt Pathway in Lung Cancer

P

P

P

PIP3

P85-α

P110-α

PIP2

SH2

P

P

P

PI3K

AKT

P

P

PTEN

Endothelial Cell


Akt is a downstream regulator
Akt 15q25 is a Downstream Regulator

Growth,

Translation

P

mTOR

P

Apoptosis

AKT

BAD

P

P

MDM2

p53

Nucleus


Flj10540 is an oncogene
FLJ10540 Is An 15q25Oncogene

Oncogene

Proto-Oncogene

Cancer Cell


Vegf a upregulates flj10540
VEGF-A 15q25Upregulates FLJ10540

(Chen et al., 2009)


Flj10540 mediates cell migration and invasion through pi3k akt
FLJ10540 Mediates Cell Migration and Invasion Through PI3K/ 15q25Akt

Giemsa-Stained Cells

  • (Chen et al., 2009)


Recap flj10540 missing link in pi3k akt
Recap: FLJ10540 Missing Link in PI3K/ 15q25Akt

VEGF-A

P

PI3K

P

P

PIP3

P85-α

P110-α

PIP2

SH2

P

P

P

FLJ10540

AKT

P

VEGFR

P

PTEN

Endothelial Cell


Imatinib is a tki
Imatinib 15q25 is a TKI

Binds to ATP binding site of many enzymes:

p-PDGFR-β Inhibitor

Reduced IFP, Hypoxia

Decreased VEGF Expression

http://www.medicinescomplete.com/mc/martindale/2007/images/MRT9229C001.gif


Imatinib targets ifp and hypoxia
Imatinib Targets IFP and Hypoxia 15q25

Normal

Tumor

http://www.medscape.com/pi/editorial/clinupdates/2000/583/art-tu02.fig04.jpg

http://www.nature.com/nm/journal/v7/n9/images/nm0901-987-F1.gif


Imatinib reduces p pdgfr and vegf expression
Imatinib Reduces p-PDGFR- 15q25β and VEGF Expression

(Vlahovic et al. 2007)


Imatinib reduces hypoxia and mvd
Imatinib Reduces Hypoxia and MVD 15q25

Vlahovic et al. 2007


Imatinib treatment
Imatinib Treatment 15q25

Imatinib

http://onctalk.com/wp-content/uploads/2008/01/angiogenesis-summary.jpg


P 15q25

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus


Treatments
Treatments 15q25

  • Dr. Ross

    • Gefinitib

  • Dr. Vildaver

    • Imatinib


Discovery of cisplatin
Discovery of 15q25Cisplatin

(Rosenberg et al., 1969)


Old model of cisplatin
Old Model of 15q25Cisplatin

Nucleus

Cisplatin

Simple Diffusion

P73

P53

NH3

NH3

Pt

C-Abl

HMG1

?

G

G

?

HMG1

Cell Cycle Arrest

&

Apoptosis


How pt drugs enter cells
How Pt Drugs Enter Cells 15q25

Pt

Transporter

protein

Transporter

protein

Pt

Pt

Pt

Pt

Pt

nucleus

(Hall et al., 2007)


Crosslinks
Crosslinks 15q25

NH3

nucleus

Pt

NH3

G

G

1,2-intrastrand d(GpG)adduct

crosslink

Cell Cycle Arrest

&

Apoptosis

(Ohndorf et al., 1999)


Pt dna adduct
Pt-DNA adduct 15q25

http://www.unc.edu/~shantanu/images/bkstcg_aacr07.png


High mobility group proteins
High Mobility Group Proteins 15q25

HMGB

Apoptosis

Pt-DNA Adduct

P73

P53

HMGB

(Stross et al., 2002)


  • * 15q25Nucleotides crosslinked

  • Bold- nucleotides contacted by the protein

(Ohndorf et al., 1999)


Phenylalanine mutations
Phenylalanine Mutations 15q25

(Ohndorf et al., 1999)


Old model of cisplatin1
Old Model of 15q25Cisplatin

?

Nucleus

Cisplatin

Simple Diffusion

P73

P53

NH3

NH3

Pt

C-Abl

HMG1

?

G

G

?

HMG1

Cell Cycle Arrest

&

Apoptosis


2 distinct regulating mechanisms
2 Distinct Regulating Mechanisms 15q25

tyrosine kinase

cisplatin

mismatch repair protein

homologue of p53

Tumor suppresor

(Gong et al., 1999)


Role of p73 in cell death
Role of p73 in Cell Death 15q25

MLH1-/- & Abl= less sensitive to CDDP , survived better than wild type in lower concentrations of CDDP

P53 knockout= less sensitive to CDDP, survived better than wild type in lower concentrations of CDDP

(Gong et al., 1999)


New model of cisplatin
New Model of 15q25Cisplatin

Nucleus

Cisplatin

Simple Diffusion

P53

P73

NH3

NH3

P

Transporter

Proteins

Pt

C-Abl

Cell Cycle Arrest

&

Apoptosis

HMG1

G

G

ATM

HMG1


EGF 15q25

ERBB2

Cisplatin

Imatinib

Protein

Cascade

Gefitinib

EGFR

P

?

Nucleus

?


P 15q25

VEGF-A

EGF

MET

P

ERBB2

P

PI3K

Imatinib

Cisplatin

Gefitinib

Protein

Cascade

Protein

Cascade

EGFR

P

AKT

PDGFR

P

Nucleus


Cocktail of drugs

? 15q25

Cocktail of Drugs

http://www.specialityformulations.com/pcat-gifs/products-small/imatinib.jpg

http://immunodefence.com/ii/gefitinib.gif

http://www.themesotheliomalibrary.com/cisplatin.jpg


Current future hypotheses
Current & Future Hypotheses 15q25

  • New plasma membrane proteins have unique mechanisms and effects on NSCLC

  • Gefitinib effectively inhibits particular EGFR mutants

  • SiRNA could be used as a possible treatment for various mutated proteins


Future studies
Future Studies 15q25

  • How does cisplatin enter the nucleus?

  • Roles and mechanisms behind the various mutated proteins involved in lung cancer

  • New drugs , secondary mutations


Acknowledgements
Acknowledgements 15q25

Professor Sleiter

Schmooing yeast!!!

?


Acknowledgements1
Acknowledgements 15q25

Dr. DebBurman


Acknowledgements2
Acknowledgements 15q25

Mike Fiske


References
References 15q25

Abid MR, Guo S, Minami T, Spokes KC, Ueki K, et al. (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. ArteriosclerThrombVascBiol 24: 294-300.

Agami, R., Blandino, G., Oren, M., and Shaul, Y. (1999). Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. Nature 399, 809-813.

Alberg AJ, Ford JG, Samet JM; American College of Chest Physicins. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007; 132:29S-55S.

Alberts, B., Bray, D., Hopkin, K., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. 2004. Essential Cell Biology. Garland Science. New York, pp740.

Chanock, Stephen J., Hunter, David J. 2008. When the smoke clears. Nature. 452: 537-538.

Chen, C.H., Lai, J.M., Chou, T.Y., Chen, C.Y., Su, L.J., Lee, Y.C., Cheng, T.S., Hong, Y.R., Chou, C.K., Whang-Peng, J., Wu, Y.C., and Huang, C.Y. (2009). VEGFA upregulates FLJ10540 and modulates migration and invasion of lung cancer via PI3K/AKT pathway. PLoS ONE 4, e5052.

Chen, Y.R., Fu, Y.N., Lin, C.H., Yang, S.T., Hu, S.F., Chen, Y.T., Tsai, S.F., and Huang, S.F. (2006). Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants. Oncogene 25, 1205-1215.

Engelman, J.A., Janne, P.A., Mermel, C., Pearlberg, J., Mukohara, T., Fleet, C., Cichowski, K., Johnson, B.E., and Cantley, L.C. (2005). ErbB-3 mediates phosphoinositide 3- kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl. Acad. Sci. U. S. A. 102, 3788-3793.

Ferrara, N. and Kerbel, R.S. (2005). Angiogenesis as a therapeutic target. Nature 438, 967.

Franks, L.M. and Teich, N. (1986). Introduction to the Cellular and Molecular Biology of Cancer (New York:Oxford University Press).

Gao, B., Lee, S.M., and Fang, D. (2006). The tyrosine kinase c-Abl protects c-Jun from ubiquitination-mediated degradation in T cells. J. Biol. Chem. 281, 29711-29718.

Hall, M.D., Okabe, M., Shen, D.W., Liang, X.J., and Gottesman, M.M. (2008). The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu. Rev. Pharmacol. Toxicol. 48, 495-535.

Helotera, H. and Alitalo, K. (2007). The VEGF Family, the Inside Story. Cell 130:591-592

Hung, Rayjean J. et al. 2008. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 452: 633-637.

Huang, J.C., Zamble, D.B., Reardon, J.T., Lippard, S.J., and Sancar, A. (1994). HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. Proc. Natl. Acad. Sci. U. S. A. 91, 10394-10398.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. (2008) Cancer statistics, 2008. CA Cancer J Clin 58: 71-96.


References1
References 15q25

  • Johnson DH, Blot WJ, Carbone DP, et al. Cancer of the lung_Non-small cell lung cancer and small cell lung cancer. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKena WG. Clinical Oncology. 4th ed. Philadelphia, Pa: Churchill Livingstone Elsevier: 2008: chap 76.

  • Jones, R.B., Gordus, A., Krall, J.A., and MacBeath, G. (2006). A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 439, 168-174.

  • Kwak, E.L., Sordella, R., Bell, D.W., Godin-Heymann, N., Okimoto, R.A., Brannigan, B.W., Harris, P.L., Driscoll, D.R., Fidias, P., Lynch, T.J. et al. (2005). Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc. Natl. Acad. Sci. U. S. A. 102, 7665-7670.

  • McKay, James D. et al. 2008. Lung cancer susceptibility locus at 5p15.33. Nature Genetics. 40(12): 1404-1406.

  • Moyer JD, Barbacci EG, Iwata KK, Arnold L, Boman B, et al. (2006) Induction of apoptosis and cell cycle arrest by CP-358,774, and inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57: 4838-4848.

  • Ohndorf, U., Rould, M., He, Q., Pabo, C., Lippard (1999). Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins. Nature. 399: 708-712.

  • Pedersen, M.W., Pedersen, N., Ottesen, L.H., and Poulsen, H.S. (2005). Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII. Br. J. Cancer 93, 915-923.

  • Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K (2001) Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res 61: 2929-2934.

  • Poklar, N., Pilch, D.S., Lippard, S.J., Redding, E.A., Dunham, S.U., and Breslauer, K.J. (1996). Influence of cisplatinintrastrandcrosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex. Proc.Natl. Acad. Sci. U. S. A. 93, 7606-7611.

  • Rikova, K., Guo, A., Zeng, Q., Possemato, A., Yu, J., Haack, H., Nardone, J., Lee, K., Reeves, C., Li, Y. et al. (2007). Global Survey of Phosphotyrosine Signaling Identifies OncogenicKinases in Lung Cancer. Cell 131, 1190- 1203.

  • Ruddon, R.W. (2007). Cancer Biology: Fourth Edition (New York: Oxford University Press).

  • Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH (2002) Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346: 92-98.

  • Shilo, B., Yarden, Y. (2007). Snap Shot: EGFR Signaling Pathway. Cell.131, 1018e1-1018e2.

  • Stros, M., Ozaki, T., Bacikova, A., Kageyama, H., and Nakagawara, A. (2002). HMGB1 and HMGB2 cell-specifically down-regulate the p53- and p73-dependent sequence-specific transactivation from the human Bax gene promoter. J. Biol.Chem. 277, 7157-7164.

  • Thorgeirson, Thorgeir E. et al. 2008. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 452: 638-642.

  • Vlahovic G, Rabbani ZN, Herndon II JE, Dewhirst MW, Vujaskovic Z (2006) Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation. Br J Cancer 95: 1013– 1019.

  • Yarden, Y., and Sliwkowski, M.X. (2001). Untangling the ErbBsignalling network. Nat. Rev. Mol. Cell Biol. 2, 127-137.

  • Yuan, Z.M., Shioya, H., Ishiko, T., Sun, X., Gu, J., Huang, Y.Y., Lu, H., Kharbanda, S., Weichselbaum, R., and Kufe, D. (1999). p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399, 814-817.

  • Yun, C.H., Mengwasser, K.E., Toms, A.V., Woo, M.S., Greulich, H., Wong, K.K., Meyerson, M., and Eck, M.J. (2008). The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. U. S. A. 105, 2070-2075.


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