Transcript The Molecular Basis of Cancer

Disclosure/Disclaimer
The Molecular Basis of Cancer Educational Series is not intended to
promote any cancer agent or class approved by the FDA
or currently under clinical development.
The contents of these slide presentations are owned solely by
Genentech; any unauthorized uses are prohibited. These programs are
intended to provide general information about the molecular basis of
cancer, not medical advice for any particular patient.
The information is presented on behalf of Genentech, and is consistent
with FDA guidelines.
BIO0001698902
 2014 Genentech USA, Inc. All rights reserved.
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Common genetic and molecular alterations in
lung• Acancer
point mutation in the epidermal growth factor receptor (EGFR) gene (L858R) can
Notes
result in abnormal kinase activation of the EGFR protein1
• Translocations within chromosome 2p result in the fusion of echinoderm
microtubule-associated protein-like 4 (EML4) to anaplastic lymphoma
kinase (ALK); this mutation has potent oncogenic activity in lung cancer2
• Amplification of a region on chromosome 7—which encodes the EGFR gene—can
result in overexpression of this gene3
• Mutation, amplification, deletion, methylation, or post-translational modification along
the PI3K/AKT/mTOR signaling pathway can dysregulate cell growth and proliferation4
• Interaction between pathways, such as cross-talk through numerous points of convergence
between the PI3K/AKT/mTOR and RAS/RAF/MEK signaling cascades, enable cell growth,
Point mutation
division, survival, and the development of therapeutic resistance in lung cancer4
• By the time tumors are detected in the clinic, tumor cells have already evolved
Singlemechanisms
base pair of dysregulating the immune response and escaping destruction5
Evasion of
Translocations in
Amplification of
Signaling pathway
mutation in the
immune
chromosome 2p
EGFR
alterations
EGFR gene
destruction
References:
1. Yatabe Y, Mitsudomi T. Epidermal growth factor receptor mutations in lung cancers. Pathol Int. 2007;57:233-244.
Chromosome
7 Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer
2. Shaw AT,
who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253.
3. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al. Epidermal growth factor receptor in non–small-cell lung carcinomas:
correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol. 2003;21:37983807.
4. Heavey S, O’Byrne KJ, Gately K. Strategies for co-targeting the PI3K/AKT/mTOR pathway in NSCLC.
Cancer Treat Rev. 2014;40:445-456.
5. Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in 2012.
CA Cancer J Clin. 2012;62:309-335.
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Notes
EML4-ALK fusion mediates aberrant ALK activation
• The ALK gene is located on chromosome 2 and codes a
transmembrane receptor TK in the insulin receptor superfamily
RAS
AKT
• Expression of native ALK in adult human tissues seems to
be restricted to the small intestine, testes, and nervous
system, and some evidence suggests it plays
a role in
PI3K
Inversion
Shc
Grb2
neurological development
Sos
• Under normal conditions, activation of ALK occurs via
ligand-induced dimerization, which leads to autophosphorylation
Raf
• Activation of downstream
signaling pathways—including Janus kinase
(JAK)/signal transducer and activator of transcription (STAT),
phosphatidylinositol
3-kinase (PI3K)/AKT, and
MEK
Inversion
MAPK (MAPK)—leads to cell proliferation
mitogen-activated protein kinase
and differentiation
Inversion
Inversion
• When fused with EML4, it can lead to constitutive activation,
even without the presence of ligands
Reference:
Camidge DR, Doebele RC. Treating ALK-positive lung cancer—early successes and future
challenges. Nat Rev Clin Oncol. 2012;9:268-277.
Proliferation
↓ Apoptosis
ALK=anaplastic lymphoma kinase; EML4=echinoderm microtubule-associated protein-like 4; Grb2=growth factor receptor-bound protein-2; MAPK=mitogen-activated protein kinase;
MEK=mitogen-activated protein kinase kinase; PI3K=phosphatidylinositol 3-kinase; Shc=Src homology 2 domain containing transforming protein 1; Sos=son of sevenless.
Camidge DR, Doebele RC. Nat Rev Clin Oncol. 2012;9:268-277.
Survival
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Targeting the EGFR pathway with SMIs:
Preventing phosphorylation events
EGFR
EGFR
Notes
EGFR
HER3
• Members of the
family
established
therapeutic targets
SosareRas
Grb2
Sos Grb2
ShcHER
Shc
AKT
• Additional therapeutic strategies are being developed that PI3K
target
PDK1
HER family receptors and intracellular signaling proteins
Raf (TKIs) that prevent signal
• Small-molecule tyrosine kinase inhibitors
transduction via the TK domain of the receptor are one mechanism
for targeting receptors
mTOR
• Other small-molecule inhibitors target intracellular
MEK
signaling intermediates
MAPK
GSK3ß
NFκB
Cyclin D1
BAD
p27
Reference:
Rowinsky EK. The ErbB family: targets for therapeutic development against
cancer and therapeutic strategies using monoclonal antibodies and tyrosine
kinase inhibitors. Annu Rev Med. 2004;55:433-457.
↑ Survival
Cell-cycle
control
Angiogenesis
↓ Apoptosis
Proliferation
BAD=Bcl-2–associated death promoter; EGFR=epidermal growth factor receptor; Grb2=growth factor receptor-bound protein 2; GSK3β=glycogen synthase kinase 3 beta; HER3=human epidermal growth factor receptor-3; MAPK=mitogen-activated protein kinase;
MEK=mitogen-activated protein kinase kinase; mTOR=mammalian target of rapamycin; NFκB=nuclear factor kappa–light-chain enhancer of activated B cells; PDK1=phosphoinositide-dependent kinase-1;
PI3K=phosphatidylinositol 3-kinase; Raf=rapidly accelerating fibrosarcoma; Ras=rat sarcoma; SMI=small molecule inhibitor; Shc=Src homology 2 domain containing transforming protein 1; Sos=son of sevenless.
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Olayioye MA, et al. EMBO J. 2000;19:3159-3167.
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