2014 genentech usa, inc. all rights reserved. 1 disclosure/disclaimer the molecular basis of cancer...
TRANSCRIPT
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2014 Genentech USA, Inc. All rights reserved.1
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
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2 2014 Genentech USA, Inc. MBoC Program
Common genetic and molecular alterations in lung cancer
Point mutation
Single base pair mutation in the EGFR gene
Chromosome 7
Evasion ofimmune
destruction
Translocations in chromosome 2p
Amplification of EGFR
Signaling pathwayalterations
• A point mutation in the epidermal growth factor receptor (EGFR) gene (L858R) can 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, 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 mechanisms of dysregulating the immune response and escaping destruction5
References:1. Yatabe Y, Mitsudomi T. Epidermal growth factor receptor mutations in lung cancers. Pathol Int. 2007;57:233-244.2. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer
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;21:3798-3807.
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.
Notes
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3 2014 Genentech USA, Inc. MBoC Program
EML4-ALK fusion mediates aberrant ALK activation
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.
Proliferation Survival
MEK
Raf
Sos Grb2 Shc
RAS
PI3K
MAPK
Inversion AK
T
↓ Apoptosis
InversionInversionInversion
• The ALK gene is located on chromosome 2 and codes a transmembrane receptor TK in the insulin receptor superfamily
• 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 neurological development
• Under normal conditions, activation of ALK occurs via ligand-induced dimerization, which leads to autophosphorylation
• Activation of downstream signaling pathways—including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), phosphatidylinositol 3-kinase (PI3K)/AKT, and mitogen-activated protein kinase (MAPK)—leads to cell proliferation and differentiation
• 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.
Notes
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4 2014 Genentech USA, Inc. MBoC Program
AK
TPDK1
PI3K
Cyclin D1
p27
BAD
GSK3ß
NFκBmTOR
MAPK
Targeting the EGFR pathway with SMIs:Preventing phosphorylation events
Cell-cyclecontrol
↓ Apoptosis
Ras Sos Grb2 Shc
MEK
Raf
↑ Survival
EGFR HER3
ProliferationAngiogenesis
EGFR
SosGrb2Shc
EGFR
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. Olayioye MA, et al. EMBO J. 2000;19:3159-3167.
• Members of the HER family are established therapeutic targets
• Additional therapeutic strategies are being developed that target HER family receptors and intracellular signaling proteins
• Small-molecule tyrosine kinase inhibitors (TKIs) that prevent signal transduction via the TK domain of the receptor are one mechanism for targeting receptors
• Other small-molecule inhibitors target intracellular signaling intermediates
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.
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