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Adenocarcinoma of the lung: a molecular perspective. Rolf Stahel Zürich, Switzerland. Lugano, 8.7.07. Morpholgical classification of lung cancer. Small cell lung cancer (15%) Non-small cell lung cancer (85%) Squamous cell carcinoma Adenocarcinoma Bronchoalveolar carcinoma

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Adenocarcinoma of the lung a molecular perspective l.jpg

Adenocarcinoma of the lung:a molecular perspective

Rolf Stahel

Zürich, Switzerland

Lugano, 8.7.07


Morpholgical classification of lung cancer l.jpg
Morpholgical classification of lung cancer

  • Small cell lung cancer (15%)

  • Non-small cell lung cancer (85%)

    • Squamous cell carcinoma

    • Adenocarcinoma

      • Bronchoalveolar carcinoma

    • Large cell carcinoma

    • Rarer entities


Changing distribution of lung cancer histology u texas galvaston l.jpg
Changing distribution of lung cancer histology (U Texas Galvaston)

Mary Wahbah, Ann Dign Pathol, 2007


Oncogene mutations lung adenocarcinoma l.jpg
Oncogene mutations Galvaston)lung adenocarcinoma

  • About 50% of lung adenocarcinoma harbor somatic mutations of six genes that encode proteins in the EGFR signaling pathway:

    • KRAS mutations

    • EGFR mutations

    • Her-2 mutations

    • Her-4 mutations

    • BRAF mutations

    • Phosphatidylinositol 3-kinase (PI3K) mutations


Egfr downstream signaling l.jpg
EGFR: downstream signaling Galvaston)

EGFR, HER2

Cell membrane

SOS

EGFR-TK

RAS

ATP

ATP

PI3K

GRB2

RAF

P

MAPK

Akt

STAT

MEK

EGFR-TKpathways

Gene transcriptioncell-cycle progression

Nucleus

Proliferation

Resistance to

apoptosis

Invasion

Metastasis

Angiogenesis


Ras mutations l.jpg
Ras mutations Galvaston)

  • 1979-1981: Cloning of H-ras and K-ras

  • 1987: Rodenhuis, NEJM 1990: Slebos, NEJM: K-ras mutation in 30% of lung adenocarcinoma. Associaton with smoking. Poor prognostic factor in resected tumors

  • 1989-1990:Isoprenylation (farnesyl-tranferase) necessary for biological activity


Ras mutation in nsclc l.jpg
RAS mutation in NSCLC Galvaston)

  • Induction of lung adenocarcinoma in the mouse model by conditional activation of mutated KRAS (Meuwissen, Oncogene 2001)

  • Meta-analysis of 23 clinical studies with mutational data: HR 1.4 (CI 1.18-1.65)(Mascaux, Br J Cancer 2005)

  • Adjuvant cisplatin/vinorelbine subgroup analysis according to ras mutation: No apparent benefit in patients with ras mutated tumors (however not significant in interaction analysis)(Winton, NEJM 2005)

  • Lack of sensitivity of K-ras mutated tumors to gefitinib or erlotinib(Pao, PLoS 2005)


Slide8 l.jpg

Gefitinib responders Galvaston)

Non-responders

EGFR mutations

8/9

0/7


Case report l.jpg
Case report Galvaston)

75 y/o man retired, held many jobs from working as driver, attendant at gasoline station to sexton. Hobby trumpet

  • 2/06 follow-up CT one year after TUR-P: solitary lesion L lower lobe. 3-months follow-up CT: Increasing seize

  • 6/06 thoracoscopic wedge resection abandoned because of non-small cell lung cancer with carcinomatosis of pleura: referral for palliative chemotherapy

  • Histology: adenocarcinoma

  • Smoking history: Never smoker

  • EGFR mutation analysis: deletion in exon 19 (delL747-E749, A750P)


Case report10 l.jpg
Case report Galvaston)

  • 7/06: erlotinib and bevacizumab (SAKK 19/05)

10.7.06

29.8.06

22.6.07


Egfr mutations in lung adenocarcinoma l.jpg
EGFR mutations in lung adenocarcinoma Galvaston)

Sharma, Nat Rev Cancer, 2007


Egfr mutations and adenocarcinoma histology l.jpg
EGFR mutations and adenocarcinoma histology Galvaston)

Yatabe and Mitsudomi, Pathology International, 2007

Mucinous differentiation of adenocarcinoma with broncheoalveolar features correlates with absence of EGFR mutations and presence of KRAS mutations(Finberg, J Mol Diagn 2007)


Slide13 l.jpg

11 ligands each with a common Galvaston)

EGF like structure

EGF

TGF-a

Amphiregulin

Betacellulin

Epiregulin

HB-EGF

Epigen

Neuregulin 1 (NRG1)

Neuregulin 2 (NRG2)

Neuregulin 3 (NRG3)

Neuregulin 4 (NRG4)

EGF

The ErbB family

4 types of erbB receptors

ErbB1 (HER1, EGFR)

ErbB2 (HER2, neu)

ErbB3 (HER3)

ErbB4 (HER4)


Her2 and her4 mutations lung cancer l.jpg
HER2 and HER4 mutations lung cancer Galvaston)

  • HER2 mutation in 10% of lung adenocarcinomas(Stephens, Nature 04)

  • HER2 mutations mainly in adenocarcinoma with broncheoalveolar features and mutually exclusive with KRAS and EGFR mutations(Buttitta, IJC 2006)

  • Cells transfected wit mutated HER2 remain sensitive to lapatinib, but become resistant to EGFR TKIs(Wang, Cancer Cell 2006)

  • HER4 mutations in 2.3% of lung cancers (adeno and squamous cell)(Soung, IJC 2006)


Egfr downstream signaling15 l.jpg
EGFR: downstream signaling Galvaston)

EGFR, HER2, HER4

Cell membrane

SOS

EGFR-TK

RAS

ATP

ATP

PI3K

GRB2

RAF

P

MAPK

Akt

STAT

MEK

EGFR-TKpathways

Gene transcriptioncell-cycle progression

Nucleus

Proliferation

Resistance to

apoptosis

Invasion

Metastasis

Angiogenesis


Braf mutations in nsclc l.jpg
BRAF Mutations in NSCLC Galvaston)

V600E

Missense mutations in 4/35 lung adenocarcinoma cell lines and in 2/127 lung adenocarcinoma tissues (Davis, Nature 2002, Noaki, CR 2002 )

Lung-specific expression of mBRAF in mice induced MAPK pathway activation and development of lung adenocarcinomas, which were sensitive to a MEK inhibitor(Ji, Cancer Res 2007)

Expression of mBRAF induced lung adenomas in mice. For the development of adenocarcinomas additional TP53 mutation was needed. (Dankort, Genes and Development, 2007)


Egfr downstream signaling17 l.jpg
EGFR: downstream signaling Galvaston)

EGFR, HER2, HER4

  • PI3K mutations:

  • 5% NSCLC cell lines

  • 1.2% NSCLC tumors

Cell membrane

SOS

EGFR-TK

RAS

ATP

ATP

PI3K

GRB2

RAF

P

MAPK

Akt

STAT

MEK

EGFR-TKpathways

Gene transcriptioncell-cycle progression

Nucleus

Proliferation

Resistance to

apoptosis

Invasion

Metastasis

Angiogenesis


Slide18 l.jpg
Two mutually exclusive pathways to lung adenocarcinoma Galvaston)(pooled data from East Asian and western countries)

Tobacco

KRAS mutations (14%)

Smokers

Adenocarcinoma

Genetic factors ?

? Carcinogen

EGFR mutations (31%)

HER2 mutations (4%)

BRAF mutations (1%)HER4 mutations (rare)

Never

Smokers

Gazdar, IASLC Workshop 2006


Mutational profiling of resected lung adenocarcinomas l.jpg
Mutational profiling of resected lung adenocarcinomas Galvaston)

235 lung adenocarcinomas from MSKCC tissue bank, 39 kinases:

  • EGFR mutations: 6%

  • BRAF mutations: <1%

  • PI3K mutations: 2%

  • KRAS mutations: 12%

  • 1 not previously described mutation of the fibroblast growth factor receptor-4 (FGFR4)

    Conclusion: The majority of gain of function mutations in lung adencocarcinoma have been identified

Marks, PLOS 2007



Correlation between mutation status and tki sensitivity her2 overexpression confers sensitivity l.jpg
Correlation between mutation status and TKI sensitivity: Galvaston)HER2 overexpression confers sensitivity

1000

100

T790M

10

PTEN absent

TKI IC50 (mM)

1

HER2 amplified

0.1

0.01

mEGFR

mKRAS

mBRAF

WT

Mutation status

Gazdar, IASLC Workshop 2006


Met amplification leads to gefitinib resistance in lung cancer by activating erbb3s signaling l.jpg
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3s signaling

Concurrent inhibition of MET by PHA665725 und EGFR suppresses growth of MET amplified, EGFR mutant adenocarcinoma cell line

Engelman, Science 2007


Findings associated with resistance to egfr tki l.jpg
Findings associated with resistance to EGFR TKI cancer by activating ERBB3s signaling

  • Lack of activating activating mutations in EGFR exons 18–21

  • K-ras mutation: Screening of cell lines and introduction of mutated KRAS into EGFR mutated cell line(Pao, PLoS 2005, Uchida, Cancer Sci 2007)

  • Presence of T790M mutation: 50% of tissue samples from patients with acquired gefitinib resistance(Kosaka, Clin Cancer Res 2006)

  • ADAM17 mediated heregulin autocrine loop inducing ERBB2/3 signalling(Zhou, Cancer Cell, 2006)

  • Amplification of MET: 22% of patients with acquired gefitinib or erlotinib resistance(Engelman, Science 2007)


Slide24 l.jpg
Molecular classification of lung cancer and morphology: cancer by activating ERBB3s signalingTerminal respiratory unit (TRU) derived adenocarcinoma

TRU

Yatabe, Cancer Chemother Pharmacol 2006


Proposed schema of molecular classification of lung cancer l.jpg
Proposed schema of molecular classification of lung cancer cancer by activating ERBB3s signaling

Yatabe and Mitsudomi, Pathology International, 2007


Expression profiling of adenocarcinoma and underlying genetic changes l.jpg
Expression profiling of adenocarcinoma cancer by activating ERBB3s signalingand underlying genetic changes

Takeuchi, JCO 2006


Lung mutagene model potti nejm 2006 l.jpg
Lung mutagene cancer by activating ERBB3s signaling model(Potti, NEJM 2006)

Identifying gene expression profiles predictive of recurrence after surgery


Adenocarcinoma of the lung a molecular perspective 1 l.jpg
Adenocarcinoma of the lung: cancer by activating ERBB3s signalinga molecular perspective (1)

  • 50% of tumors harbor somatic mutations of six genes encoding proteins in the EGFR signaling pathway: KRAS, EGFR, BRAF, PI3K, HER2 and HER4.

  • With the exception of PI3K mutations, they are mutually exclusive

  • The carcinogens of tumors with oncogenic mutations other than KRAS remain to be identified

  • The identification of an activating EGFR mutations has therapeutic implications today(USA 15’000 cases/y, CML and GIST 4500 cases/y each)


Adenocarcinoma of the lung a molecular perspective 2 l.jpg
Adenocarcinoma of the lung: cancer by activating ERBB3s signalinga molecular perspective (2)

  • The following genetic alterations confer resistance to EGFR TKIs: KRAS mutations, EGFR mutation T790M, MET amplification

  • The correlations between molecular and histologcial characteristics of lung tumors will lead to new proposals for the classification of lung adenocarcinoma

  • Gene expression arrays are likely to become an integral part of clinical decision making


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