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7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
http://slidepdf.com/reader/full/jr-sastia-pathogenesis-of-lung-cancer-signalling-pathways-revisi 1/24
Pathogenesis of lung cancer signallingpathways:
roadmap for therapies
Oleh : dr Sastia Rakhma
Pembimbing : dr. Nunuk Sri Muktiati, Sp.P !"
#. $rambilla, %. &a'dar. Pathogenesis of lung cancer signallingpathways: roadmap for therapies.#ur Respir ( )**+ --: /012
/+3
(O4RN%5 R#%67N&
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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• !anker paru : pembunuh utama di dunia
18yr sur9i9al 15%)
membutuhkanstrategi terapi yg lebih efektif
• 6i masa yg akan dtg terapi kanker paruakan ditargetkan pd gen atau pathwaytertentu targetted theraphy".
I. Growth promoting pathways
II. Growth inhibitory pathways
III. Apoptotic pathwaysIV. DNA repair and immortalisation genes.
)
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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#;7O5O&7 !%N!#R P%R4
• / <enis histologi kanker paru: – Small cell lung cancer S=5=",
– S>uamous cell carcinoma S==",
– %deno carcinoma %6=" – 5arge cell carcinoma
• Mayoritas kanker paru 01? dari NS=5= @+0? dari S=5=" muncul pada perokok.
• !anker paru pd non8smoker disebabkanoleh karsinogen eAogen yg blmteridentiBkasi.
-
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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7. !#5%7N%N P%6% GR!"#$"I&'(A"R IGNA((ING *A"#!A
• &rowth Stimulatory Pathways terdiridari:
A.+pidermal growth ,actor receptor-+GR) signalling pathway
/.Anaplastic lymphoma 0inase ,sion proteins
2."hyroid transcription ,actor 1 -"I"1)
D.&2 ,amily
/
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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A. +pidermal growth ,actorreceptor -+GR) signalling
pathway
1
;erdiri dari:a" #pidermal growth factor
receptor deregulationb" Mutations in other #&CR
signalling pathway genesc" P7-!
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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/. Anaplastic lymphoma 0inase
,sion proteins
• Peranan A(3 ,sion protein belumsepenuhnya dipahami didugamemiliki peranan dlm mengakti9asi
R%S mengaktifkan cellgrowth4dierentiation4 sr6i6al)
D
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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2. "hyroid transcription ,actor 1
-"I"1)
• "hyroid transcription ,actor 1 ;7;C <uga dikenal dg N!E)8" F faktortranskripsi yg penting uG
perkembangan peripheral airways.
• Mrp marker spesiBk uG tumor) ygberasal dari terminal respiratory
nit peripheral AD2s
3
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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6. MH= family
• "he &2 gene ,amily MH=, N8MH=,58MH=" mengontrol pertumbuhansel @ apoptosis.
• 58 @ N8MH= spesiBk uGneroendocrine lng tmors,inclding 2(2 7 large cell
neroendocrine carcinoma -(2N+2)).
0
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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II. A/NR&A(I"I+ IN "'&'R'**R+R G+N+ *A"#!A
• - macam tumor suppressor gen:
a. P1-
b. PD
c. Serine G threonine kinase
a. ;he p1- pathway
•. p1- men<aga stabilitas gen, dgmen<adi sensor kerusakan 6N%,akti9asi oncogen, @ hipoksia.
+
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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*
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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%$NORM%57;7#S 7N ;4MO4RS4PPR#SSOR &#N# P%;IJ%HS )"
• p1- : gen yg paling sering bermutasipd kanker paru
• Mutasi P1- sangat berhubungan dgeksposur thd karsinogen rokok
• %da ) regulator P1-: Mdm) @p/%RC
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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%$NORM%57;7#S 7N ;4MO4RS4PPR#SSOR &#N# P%;IJ%HS -"
b. pD7N!/Gcyclin 6GRb pathway
• Rb : mengakti9asi p) cyclindependent kinase =6!" inhibitor &
arrest
c. ;he serineGthreonine kinase gene
• "311 adl barier ter<adinya plmonary
tmorigenesis4 controlling initiation4dierentiation o, cell polarity @ metastasis
)
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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777. !#&%&%5%N %POP;OS7S
;erdiri dari:
a. &itochondrial apoptosis
b. Death receptor dereglation
c. 2ell immortalisation and telomerase acti6ation
a. &itochondrial apoptosis -/a89/cl$:)
•. $cl8) anti8apoptotic" @ $aA pro8apoptotic" F faktorkunci mitochondrial apoptosis. Mengontrol permeabilitas
membran luar mitokondria
melepas0an cytochrome 24the point o, no retrn untuk apoptosis sel
•. /cl$: ↑ pd hampir semua S=5=, 5=N#= @ sebagian kecilNS=5=
-
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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b. 6eath receptor deregulation
• 6eath receptor Cas" : mengakti9asisignalling pathway apoptosis
• Cas <umlahnya sangat sedikit padaNS=5= bahkan hampir tidak adapada beberapa S=5=
/
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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1
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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c. =ell immortalisation and telomeraseacti9ation
• ;elomeres adalah susunan berulang yg
terletak pd u<ung kromoson eukariotik;;%&&&" yg berperan dalam mencegahend8to8end fusion and eAonucleaseeAcision
• ;elomeres makin memendek setelahpembelahan sel membatasi umur hidupsel
D
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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7K. #P7&#N#;7= =I%N&#S 7N 54N&
=%N=#R
• %ntara lain:
1.DNA methylation
).Perubahan pada protein histon;.Gene reglation by micro$RNA
-miRNA).
3
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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#P7&#N#;7= =I%N&#S 7N 54N&
=%N=#R )"
. 6N% methylation and lung cancer
• #pigenetics : kelainan ekspresi gen ygditurunkan yang tidak disebabkan oleh
perubahan urutan 6N%.
• #pigenetic marker: 6N% methylation
• Methylation dimulai pada awal
patogenesis kanker paru. ;erdeteksi pdsputum perokok. displasia F resikotinggi"
0
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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#P7&#N#;7= =I%N&#S 7N 54N&
=%N=#R -"
). Perubahan pada protein histon
• Perubahan pada protein histondiduga berperan pada progresi9itaskanker, karena ditemukan susunanprotein histon yang kacaudibandingkan dengan sel normal
+
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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#P7&#N#;7= =I%N&#S 7N 54N&
=%N=#R /"
-. miRN% in lung cancer
• miRN% berperan dalam mengaturekspresi gen
• miRN% dapat berfungsi sebagaionkogen dan tumor supresor gen
/. Mitochondrial mutations
• Mutasi mitokondrial muncul saat awalselama pre8neoplasia dan dapatdigunakan sebagai biomarker kanker
)*
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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!anker paru pada orang yang tidak pernahmerokok: apakah merupakan penyakit yangberbedaL"
• Merokok adalah penyebab utama mayoritaskanker paru, tetapi )1 ? dari kasus kanker parutdk berhubungan dg merokok.
• !arsinogen pd rokok mempengaruhi <alannafas proAimal @ distal menyebabkan semuabentuk kanker paru
• !anker pd non8perokok: muncul pd distalairways @ histologi pd umumnya %6=
)
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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• Iipotesa umum menganggap bahwakanker paru pada pasien yang tidakpernah merokok adalah disebabkan
karena menghirup asap rokok darilingkungan yang merupakankarsinogen yang lemah".
• Penelitian terbaru menemukanperbedaan pola mutasi pasienperokok dan non8perokok
))
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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• ;erdapat perbedaan klinis antarakanker paru pada pasien non perokokdan responnya pada targetted
therapies.
)-
7/23/2019 JR Sastia - Pathogenesis of Lung Cancer Signalling Pathways - Revisi
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)/
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