Molecular Signaling and Cancer:

Relevance to RT

Bill McBride
Dept. Radiation Oncology
David Geffen School Medicine
UCLA, Los Angeles, Ca.
wmcbride@mednet.ucla.edu

WMcB2008

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Objectives:
Know how ligands work through receptors to
activate phosphorylation /dephosphorylation
reactions leading to gene transcription
Know how dysregulation of these pathways
leads to cancer
Know how radiation-induced signal transduction
pathways intersect with those altered in cancer
to affect intrinsic radiosensitivity

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 Signaling
Signal transduction evolved to allow single cells to respond to their
extracellular environment.
It became more sophisticated as metazoans needed mechanisms
to allow
communication between cells within tissues and between
tissues to allow
morphogenesis
wound healing,
recognition and elimination of microbes,
maintenance of homeostasis.

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 Types of Signals
External microenvironmental physiological signals
Adjacent cells, extracellular matrix, cytokines and growth factors,
hormones, glucose, amino acids, ions, etc.
External microenvironmental pathological signals
Danger-associated molecular patterns (DAMPs)
Pathogen-associated molecular patterns (PAMPs)
Inflammatory and immune cells
Internal homeostatic signals
Response to DNA and mitochondrial damage, ROS, hypoxia,
metabolism, etc.
Most signals are sent through ligand binding to specific cell-surface
receptors, allowing multiple extracellular stimuli to be distinguished

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 Multiple Signaling Pathways are
Integrated to Make a Response
Peptide hormones
Odorants
Chemoattractants
Neurotransmitters
Taste Ligands

G-proteinR
Growth Factors Hormones
Lipid kinases
Steroid R
Protein kinase R Cadherins Extracellular
GTP GDP matrix
Integrins
Tumor necrosis TNFR
Factor family family Pathogen
Associated
Toll-likeR Molecular Patterns
Cytokines CytokineR Nucleus Nucleus
(PAMPs)
Damage
GlucoseR/
Associated
Ion channels
Molecular Patterns
(DAMPs)

Multiple signals are integrated to generate an appropriate biological

response, whether it be cell death/ survival, cell cycle arrest/ progression,
glycolysis/aerobic metabolism, DNA repair/stability
Signaling pathways affect radiation responses
Radiation IS a signal WMcB2008

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 The Initial Step is Receptor Activation by
Ligand-Induced Oligomerization
Inactive Receptors Activated Receptors

RTK (EGFR, PDGFR) Cytokine Receptor

P
P
P

P
P
P ATP

P
P
P

P
P
autophosphorylation

P
ADP

leads to activation of receptor kinases or conformational changes that

allow adapter proteins that bind to activate cascades
Receptors can co-associate with others to synergize eg ErbB1 and 3 -
may be important in cancer escape from targeting
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 Signals Change mRNA and
Protein Levels
Transcriptional activation
Post-transcriptional mRNA stabilization
AU rich UTRs
Translational control mechanisms
Post-translational protein destabilization and stabilization
phosphorylation, ubiquitination, acetylation, oxidation, nitrosylation
Protein degradation
Stabilization of mRNA and protein expression allow rapid
responses - immediate early genes - fos, jun, GM-CSF, TNF-
, p53, IkB, etc.

IR can cause ALL of these!

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 Major Players - Kinases

Tyrosine kinases (100 genes)

Growth Factor Receptors (RTKs; 60 genes)
Cytoplasmic (35-40 genes) Jak, Src, Fak, Tec
Serine/threonine kinases (400 genes)
MAP Kinases, TGF-R, PKC, ATM
Dual specificity kinases
MEK
Phosphatases (eg PTEN, CDC25) control phosphorylation.

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 A Few Examples - RTKs
Epidermal Growth Factor Insulin Growth Factor Receptor
Receptor family Family
erbB1 (c-erbB) IGFR-1 (c-ros)
erbB2 (neu)
erbB3 Neurotrophins
erbB4 NGFR (trk-A)
BDNFR (trk-B)
Fibroblast Growth Factor
Receptor family NT3 R (trk-C)
FGFR-1(fig)
FGFR-2(K-sam)

Platelet Derived Growth Factor

Receptor family
CSF-1R (c-fms)
SLF R (c-kit)

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 Phosphorylation
Alters activity of enzymes initiating cascades
eg MAP kinase pathway initiated by activation of EGFR
by auto-phosphorylation.
Induces DNA binding
STAT and c-jun transcriptional activities
Changes subcellular localization of proteins
e.g. recruitment of adaptor to activated receptors,
nuclear localization of hormone receptors
Changes protein stability
phosphorylation leads to degradation or stabilization -
p27, IkB, p53, etc .

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 Molecular Features of Cancer
Mutations in molecular signaling pathways leading to
Self-sufficiency in growth factor signaling (ligands or
receptors)
Loss of response to anti-proliferative signals
Evasion of programmed cell death
Increase in replicative potential (telomeres)
Promotion of tissue invasion and metastasis
Sustained angiogenesis
Amplified by DNA repair abnormalities and genomic
instability
Hanahan D, Weinberg RA, Cell 57-70, 2000.

Overall decrease in cell loss factor

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 Driver mutations in protooncogenes give
oncogenes that generally cause gain in
function.
Tumor suppressor genes are the brakes.
Mutations in these cause loss of function and
generally both alleles need to be affected.
Activated oncogenes and loss of tumor
suppressor genes cause replication stress and
increased DNA damage, which results in tumor
progression

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 Tumor cells become addicted to the mutated molecules and
pathways they need for their existence
This is good news because targeting these critical molecules can
have dramatic consequences
The bad news is that the mutation rates often allow variants to
escape
Although the steady state of the tissue cells is disturbed, there is
still a lot of cell loss.
Cancer stem cells exist that may be a small minority of the
population. They may not be the targeted by the chosen therapy.
Rapid tumor regression may not mean much if it represents loss of
the non-stem cell population
Cancer stem cells are responsible for tumor regrowth and treatment
failure

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 Oncogenes
The first oncogene (src) was discovered in 1970 in a chicken retrovirus. In
1976, Bishop and Varmus demonstrated that oncogenes were defective
proto-oncogenes that coded for normal growth and differentiation proteins
(the enemy within), for which they received the Nobel Prize in 1989.
Oncogenes are driver mutations that encode
Receptor/cytoplasmic tyrosine kinases (EGFR, PDGFR, Ras/MAPK)
Ser/thr kinases (AKT, mTOR)
Lipid kinases (PI-3K)
Transcription factors (c-MYC, STATs, c-JUN, c-FOS)
Cyclins/CDKs (Cyclin D)
Regulators of protein stability (MDM2)
Anti-apoptotic factors (BCL-2, BCL-XL)
They gain function by
Domain deletion (EGFRvIII, Her2)
Point mutation (Ras)
Translocation (BCR-Abl, Myc)
Altered subcellular localization (BCR-Abl)
Gene amplification (Myc, EGFR, Her2)

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 Oncogenic Mutations in Cancer

H-Ras K-Ras
Increased expression N-Ras Neu int-1
EGFR int-2
mos
Myc Altered protein
K-Ras
Myb
RelA
EGFR Amplification Point mutation
Insertion

Protooncogene

Translocation Deletion

Normal
protein

Altered protein
Altered Protein Increased expression EGFR, (ERB-B1), NF-B
Abl, Trk C-Myc, Bcl-2

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 Philadelphia Chromosome

Bcr (160KDa) OLI OLI

S/TK DH Rac GAP
(Breakpoint cluster region)
NTS

Abl (140KDa) SH3 SH2 TK DB AB

Bcr-Abl
ALL (190KDa) OLI OLI
S/TK SH3 SH2 TK DB AB
CML (210KDa/230 KDa) JAK1/2
Crk-L
Grb2
Nowell and Hungerford (1960) PI-3 kinase
t(9;22)(q34;q11) STAT3
CML - 95% Sos STAT5
Akt
ALL, 25-30% in adult and 2-10% in pediatrics
Abnormal signaling and localization Ras
Cyclin D1,D2,D3
ERK1/2 Bcl-xL WMcB2008

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 Imatinib/Gleevec/STI571

Druker, Sawyers and Talpaz showed that Gleevec inhibits proliferation of CML
Inhibits Abl by binding to the ATP-binding site in the kinase domain
Relapse as a result of the outgrowth of leukemic subclones with resistant BCR-
ABL mutations - treated with dasatinib

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 Myc-induced Oncogenesis
1 143 355 366 407 413 434
MB I MB II

Myc HLH LZ

Transactivation Domains DNA Binding and oligomerization

1 151

MB= Myc Boxes

BR= Basic Region
HLH= Helix-Loop-Helix
LZ= Leucine Zipper
Max HLH LZ

Mechanisms of oncogenic activation

70% of cancers have deregulated Myc
Chromosomal translocations increase c-Myc transcription
(Burkitts lymphoma and other lymphoid malignancies)
Gene amplification (AML, lung, breast, colon, brain, prostate)
Point mutations increase transactivation function (breast, ovarian,
colon)

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 C-myc Translocations in Cancer

C-Myc
gene loci

P1
P2
t(8;14)
J Ei C C

P1
P2
t(2;8)
MAREi C
Translocation

P1
P2
t(8;22)
C E

Translocations link the c-Myc gene to a region of transcriptionally active DNA

This increases c-Myc expression levels and induces aberrant proliferation
In contrast to BCR-Abl, c-Myc translocations DO NOT alter the protein structure; they
increase expression levels of the WT gene and protein

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 C-Myc translocations and disease

Translocation Genes Disease

t(8;14)(q24;q32) c-myc/IgH Burkitts lymphoma

t(2;8)(p12;q24) Igc-myc Burkitts lymphoma

t(8;22)(q24;q11) c-myc/Ig Burkitts lymphoma

t(8;14)(q24;q32) c-myc/Ig Diffuse large cell lymphoma

t(8;14)(q24;q11) c-myc/TCR, T-cell acute lymphoblastic leukemia

t(8;14)(q24;q32) c-myc/Ig Multiple myeloma
t(2;8)(p12;q24) Igc-myc Multiple myeloma
t(8;22)(q24;q11) c-myc/Ig Multiple myeloma

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 Tumor Suppressor Genes
Tumor suppressor genes are the brakes that protect cells
from carcinogenesis. A.G. Knudson first proposed for
Retinoblastoma (Rb) that loss of both alleles is required for
loss of function. This is true for most but not all Ts genes.
Hereditary Non-hereditary
Peaks at 6 months of Peaks at 2 years of
age age
Both eyes One eye affected
Heterozygous +/- +/+
Second cancers 36% Second cancers 6%
cumulative risk at 50 cumulative risk at 50
yrs of age yrs of age
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 Loss of function mutations include genes encoding
Phosphatases (eg. PTEN)
Transcription factors/repressors (p53)
Repair genes (BRCA1/2, MSH)
Cell cycle inhibitors (Rb)
Regulators of protein stability (c-Cbl)
Apoptosis inducers (Bax, Bad)
Leading to
Lack of cell cycle arrest
Decreased apoptosis
Increased metastasis

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 Multiple Mutations are Required for
Oncogenesis
Transfer of a single oncogene to a normal cell is normally
not sufficient to transform it
Loss of one allele of a Ts gene is insufficient
Cancer frequency increases with age, suggesting that
transformation of cells requires the accumulation of multiple
mutations
Most oncogenes can induce both growth and apoptosis,
indicating that transformation requires one mutation that
enhances cell growth and another that inhibits cell death
(oncogene cooperation).
Examples of two hit gene pairs in tumors:
Ras/p16 BRCA1/p53 p27/Rb Myc/p53 Myc/Ras

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 Oncogene Cooperation
(validation of the two hit hypothesis)
Expression of c-myc or ras alone fails to transform cells
C-myc Ras

P16
P19 Arf
p53

Apoptosis Senescence

Transformed focus

Expression of both c-myc and ras is transforming

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 Oncogene Expression and Radiation
Resistancy
Dose (Gy)
0 2 4 6 8 10
1

S.F.

0.1
Rat -1/ bcr-abl

Rat -1/v- fes

0.01 Rat -1/c-myc
Rat -1/v-Ha-ras
Rat -1/v-mos
Rat -1/wt-ras

Rat -1

Chiang, CS Molecular Diagnosis 3; 21, 1998

Oncogene-induced radioresistancy does not need transformation but is

based on the signal transduction pathways that are activated, and
interaction between oncogenes may negate each other
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 A Multi-step Process in Colorectal Cancer

Normal
Epithelium
APC(adenomatous polyposis coli)-catenin
Small
Increasing
Adenoma Genetic
K-Ras/BRAF Instability
Large
Adenoma
SMAD4/TGF-RII
PI3K3CA/PTEN
TP53/BAX

Carcinoma
?

Metastasis
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Percentage of Human Tumors Overexpressing EGFR

Tumor type Percentage of tumors

Bladder 31-48
Breast 14-91
Cervix/uterus 90
Colon 25-77
Esophageal 43-89
Gastric 4-33
Glioma 40-63
Head and neck 80-100
Ovarian 35-70
Pancreatic 30-89
Renal cell 50-90
Non-small-cell-lung 40-80
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 Glioblastoma multiforme
Normal
loss of 17p, TP53;
PDGF-R overexpression
Grade II
Loss of RB, 18q, 9p/IFN/p16;
CDK4, MDM2 amplification
Grade III
EGFR amplification/mutation
PDGF- overexpression,
loss of PTEN phosphatase on chr. 10
Grade IV GBM
About 40% of glioblastomas show amplification of the EGFR gene locus and about
half of these express a mutant receptor (EGFRvIII) that is constitutively active due to
an in-frame truncation within the extracellular ligand-binding domain.
EGFRvIII confers radioresistancy
15-20% of glioblastoma patients respond to small-molecule EGFR kinase inhibitors,
but only if they have an intact PTEN (phosphatase and tensin homolog).
Inhibition of mTOR, which is downstream from PTEN, with rapamycin helps.
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 EGFR Glucose
Amino acids

GLUT1

P P PIP2 PIP3
sos SH3 PH Glucose
Mutant Ras
GDP Grb2 P P SH2 PI-3K
P PTEN Akt PKA

Glucose-6-P
sos SH2
x Ras
PIP2 PIP3 LKB1
P110

GTP
P Glycolysis
Raf-1
Src AMPK

MEK
ERK1 ERK2

P P P P P P
MAPK/ERK signaling
MDM2 NF-kB BAD FKHD GSK3 mTOR rapamycin
p27
FasL
p53

SH2 binds phosphotyrosine residues

cell death/survival
SH3 binds proline-rich sequences cell cycle arrest/progression cell metabolism
PH binds lipid ligands (products of PI-3K) DNA repair/misrepair

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 Ras Oncogenic Mutations

EGFR

P
sos
Tethers Ras to
GDP Grb2 P
membrane

sos Farnesyl

GTP
x Ras Transferase
P
Raf-1 32 40 Src 192 Inhibitors
1
GTPase
GTP binding ED GTP binding HVR
MEK
ERK1 ERK2
ERK1 ERK2 MEK
CAAX Box
G12V Q61L (prenylation)

One of the most commonly mutated genes

G12V and Q61L are both involved in GTP binding
Both mutations stabilize the GTP-bound form of Ras
Both result in constitutive MAPK signaling
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 Ras Mutations in Human Tumors
*K=Kirsten; H=Harvey; N=neuroblastoma

Cancer or site of tumor Mutation Predominant

frequency % Ras isoform*

Non-small-cell lung cancer (adenocarcinoma) 33 K

K
Colorectal 44
K
Pancreas 90

Thyroid
H,K,N
53
Follicular
H,K,N
60
Undifferentiated papillary
0
Papillary
43 K,N
Seminoma

Melanoma 13 N

Bladder 10 H

Liver 30 N

Kidney 10 H

Myelodyplastic syndrome 40 N,K

Acute myelogenous leukemia 30 N

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 The PTEN Ts Gene
Genetic Mutations Gene Methylation
Glioblastoma 25-75% Glioblastoma 35%
Gastric 28% Colorectal 8%
Melanoma 20-30% Invasive Breast 48%
NHL 10% Melanoma 62%
Breast 15% Thyroid 50%
Prostate 30% Endometrium 20%
Endometrium 40-80% Prostate 50%
Ovary 5%
Lung 22%
Bladder 10%

PTEN Mutations are linked to

Cancer (eg Cowdens syndrome), invasiveness, metastasis
resistance to Herceptin, Vincristine, Adriamycin, 5-fluourouracil, Cisplatin

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 Retinoblastoma Gene Mutations in Cancer

Retinoblastoma 70%
Small Cell Lung Carcinoma 80%
Non-Small Cell Lung Carcinoma 20-30%
Osteosarcoma >50%
Multiple Myeloma 30%

Mitogens
Sherr (2000)
Cancer Research
Cyclin D 60:3689-3695
CDK 4/6
E2F Rb P E2F
P +
Rb P

S phase CDK 2
entry Cyclin E
E2F
Cyclin E
Cyclin E gene
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 TP53 (p53)
Transcription factor that also binds DNA DSBs
Degraded by binding mdm2
Mutated in >50% human cancers, in DNA binding domain
Activated by IR through ATM, DNA-PK, etc.
Increases p21 (cell cycle arrest) and Bax (apoptosis) expression
TP53 -/- mice are sensitive to DNA damage and have high incidence of tumors
TP53 mutated tumors are generally more aggressive cancers and more
radioresistant
P53 protein
1 50 102 292 323 356 363 393
TAD
MDM2 DNA binding TET CTR

Ser15 Ser33 Ser376

ATM Ser20 Ser37 Ser392
DNA-PK
ATR ATM ATR Phosphorylation sites
ATR
Chk1
Chk2 Decreased MDM2 binding

Increased
transcriptional activation
MDM2 237 260 289 333
1 108 nls 489
p53 binding

I II III Ser395 IV
ATM
(inhibition of p53 nuclear export)

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TP53 Gene Transfer Radiosensitizes Tumor
AdVluc+Irrad.
1.00 1.4
AdVp53
SKOV control
1.2
S.F.
Tumor 1.0
Diameter
0.8
0.10 (cm)
0.6
SKOV/P53 AdVp53
0.4 +irr.

0.2
irrad.irrad.
0.01 xxx xxx
0.0
0 2 4 0 10 20 30 40 50
DOSE (Gy) Time (days)

In Vitro In Vivo

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 What are the Rules?

Cancer is associated with

deregulation of the same signaling
pathways as determine intrinsic
cellular radiosensitivity
Activation of cell survival/cell cycle
progression pathways generally
result in increased radioresistance
Activation of pro-apoptotic/cell
cycle arrest pathways generally
radiosensitize
The deregulated signaling
pathways to which the cancer
becomes addicted will provide
the best targets for modifying
radioresistance

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 Summary

Intrinsic radioresistancy is driven in part by

genetically determined signaling pathways
Cancer-associated mutations will affect responses
to radiation
Oncogenic stress may activate DNA damage
responses
There is a link between DNA repair defects and
cancer
Molecular staging of cancer may predict response

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 Microarrays
Gene Microarray Tissue Microarray
Normal Tumor
40,000 probes for
20,000 genes
Compare with
common reference
sample

Cy3 Cy5 labeled

nucleotides

For staging, the aim is to define a Prognosis Classifier of <100 genes

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 Improved Molecular Staging

Current clinical and pathologic criteria are inadequate -

there is marked variation in response to therapy
amongst apparently homogeneous cancers
The hope is that molecular classification will provide
more accurate criteria for staging cancer and that this
will be more predictive of response to therapy

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 Gene Microarray Analysis

Patient samples are sorted on the basis of

similarity in expression across a set of specified
genes using hierarchical clustering algorithms
For example
Red/black/green may represent above/average/below
average expression
Dendrograms are formed to express relatedness
short branches more related than long

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 Lung
Carcinoma

67 tumors, 56
patients
Garber et al.
PNAS 98 13784
2001

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 WMcB2008

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 Retinoblastoma Protein (pocket proteins)

608 612
CDK binding site
S
A B
N E2F
C
LXCXE

56
5

7
24

35
23

37
25

80 5
S/T phosphorylation sites

79 8
78

82
6
0
9

3
2

7
78

82 1

6
81
0

1
Target for viral oncoproteins:
Adenovirus E1A
SV40 Large T
Human Papilloma Virus E7

Viral gene products as well as spontaneous and germline

mutations disrupt the Rb-E2F interaction, resulting in
increased cell cycle progression and transformation.
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 HPV
HPV is the most common sexually transmitted
disease
HPV infection is an essential factor in cervical
carcinoma and is associated with esophageal,
oropharyngeal, and anal cancer as well as penile,
vulvar and vaginal cancer.
HPV-16 is the most common HPV type associated
with a malignant phenotype regardless of origin.
What is the role of vaccines - Cervarix and
Gardasil?

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 Biochemical Features of Cancer

Invasive cancers show

Increased aerobic glycolysis (Warburg effect), even in vitro
Increased glycolysis through hypoxia
Up-regulated glucose transporters (esp. GLUT1 and3) and
hexokinases I and II
Increased uptake of FdG
Acidification of extracellular space through H+ production as
a metabolic product of glycolysis

Warburg hypothesis 1924 the prime cause of cancer is the

replacement of the respiration of oxygen in normal body cells by
a fermentation of sugar."

Otto Warburg: The Nobel Prize in

Physiology or Medicine 1931 WMcB2008

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Glucose metabolism in mammalian cells. Afferent blood delivers glucose and oxygen (on haemoglobin) to tissues,
where it reaches cells by diffusion. Glucose is taken up by specific transporters, where it is converted first to glucose-6-
phosphate by hexokinase and then to pyruvate, generating 2 ATP per glucose. In the presence of oxygen, pyruvate is
oxidized to HCO3, generating 36 additional ATP per glucose. In the absence of oxygen, pyruvate is reduced to lactate,
which is exported from the cell. Note that both processes produce hydrogen ions (H +), which cause acidification of the
extracellular space. HbO2, oxygenated haemoglobin. Gatenby and Gillies, Nature Rev Cancer
Cancer cells prefer aerobic glycolysis, even though it is less efficient, because it is faster at generating ATP, which
explains the Warburg effect. One result is up-regulation of glucose transport, which is why FDG-PET works. PI3-K,
AKT, mTOR, and AMPK are major players in the metabolic pathway driving glycolysis. WMcB2008

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 Leucine High AMP
Glutamine hypoxia
High ATP Low glucose
Exercise, TNF
glucose 2-deoxygluc
AICAR PI3K
metformin
PIP PIP3 NO
PTENAKT JAK STAT
hexokinase Pim1/2

Ribose+NADPH oxidase G-6P AMPK TSC2 BAD

NAD++ADP RHEB RHEB
GDP GTP Apoptosis
LDH-A NADH+ATP MTOR
lactate +NAD+ +Pyruvate EF2 4EBP1 Cap-dep translation

EIF4E Autophagy
Acetyl CoA
lipids citrate
Acetyl CoA proteins P70 S6K Ribosome function
TCA mitochondria

Fatty acids Amino acids

ADP ATP
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 Hypoxia/reperfusion selects for epigenetic and
genetic changes that promote
Glycolysis
Glucose uptake
Intracellular pH homeostasis (H+-ATPases)
Cell survival e.g. mtp53, NF-B, HIF-1

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 Tumor Microenvironment
Hypoxia
Growth factors/cytokines
VEGF, VEGF-R1, 2, 3, EPO, EGFR, PDGF-B, IL-1
IL-1, IL-8
Redox stress molecules
Heme oxygenase 1, metallothionein, diaphorase, GSH, Ref-1
Growth arrest molecules
GADD45, p21
Glycolytic enzymes
ALDA, PGK1, PKM, PFKL, LDHA
Signaling molecules
eNOS, PKC, COX-2

Acidic pH
H+ from glycolysis
Increased interstitial pressure
VEGF, etc.
Cellular infiltrates
May be the majority of cells in the cancer
Macrophages, fibroblasts, lymphocytes

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 WMcB2008

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 Questions:
Molecular Signaling and Cancer: Relevance to Radiotherapy

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 Which of the following mechanisms is
activated within seconds of cell irradiation
1. Transcription
2. EGFR phosphorylation
3. Cell cycle arrest
4. apoptosis

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 Which of the following is a tumor suppressor gene
1. K-Ras
2. Raf
3. Rb
4. Mos
5. Bcr-Abl

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 Which of the following is not generally
considered as a mechanism of oncogene
activation
1. Point mutation
2. Methylation
3. Gene amplification
4. Translocation

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 What protein does Imatinib target as a front-
line therapy
1. MYC
2. EGFR
3. BCR-ABL
4. K-RAS

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 The classic studies of Weinberg showed that
transformation of cells could be best
achieved with more than one oncogene.
Which did he use.
1. Ras and Raf
2. Myc and Ras
3. Jun and Fos
4. Bcr and Abl

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 What percent of glioblastomas show the
EGFRviii mutation
1. 100%
2. 75%
3. 50%
4. 25%

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 The EGFRviii mutation reflects
1. Loss of the extracellular domain of the
EGFR
2. Amplification of the EGFR gene
3. A specific point mutation in EGFR
4. A mutation leading to loss of EGFR
signaling

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 Which of the following is correct for the phosphatase and
tensin homolog (mutated in multiple advanced cancers 1)
gene (PTEN)
1. It is a receptor tyrosine kinase
2. It is mutated almost exclusively in glioblastoma tumors
3. Its loss results in high levels of phosphorylated Akt
4. Its loss results in high levels of ras signaling

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 Which of the following is NOT correct for
Ras mutations
1. Most are point mutations
2. They cause constitutive activation of the
MAP kinase pathway
3. They activate Raf
4. They block the binding of RAS to the
membrane following prenylation

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 Which of the following is NOT correct for
TP53
1. It is a transcription factor
2. It is difficult to detect in cells under normal
conditions because it is rapidly degraded
by mdm2
3. It binds to DNA breaks
4. It activates ATM to cause cell cycle arrest

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 Which of the following is a primary cause of
cervical are oropharyngeal cancer
1. TP53 mutation
2. Human papilloma virus
3. K-ras mutation
4. Loss of PTEN

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 Answers
1. NA
2. 2
3. 3
4. 2
5. 3
6. 2
7. 3
8. 1
9. 4
10. 4
11. 5
12. 2

WMcB2008

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