Entry Name Non-small cell lung cancer - Homo sapiens (human)
Description Lung cancer is a leading cause of cancer death among men and women in industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer and represents a heterogeneous group of cancers, consisting mainly of squamous cell (SCC), adeno (AC) and large-cell carcinoma. Molecular mechanisms altered in NSCLC include activation of oncogenes, such as K-RAS, EGFR and EML4-ALK, and inactivation of tumorsuppressor genes, such as p53, p16INK4a, RAR-beta, and RASSF1. Point mutations within the K-RAS gene inactivate GTPase activity and the p21-RAS protein continuously transmits growth signals to the nucleus. Mutations or overexpression of EGFR leads to a proliferative advantage. EML4-ALK fusion leads to constitutive ALK activation, which causes cell proliferation, invasion, and inhibition of apoptosis. Inactivating mutation of p53 can lead to more rapid proliferation and reduced apoptosis. The protein encoded by the p16INK4a inhibits formation of CDK-cyclin-D complexes by competitive binding of CDK4 and CDK6. Loss of p16INK4a expression is a common feature of NSCLC. RAR-beta is a nuclear receptor that bears vitamin-A-dependent transcriptional activity. RASSF1A is able to form heterodimers with Nore-1, an RAS effector.Therefore loss of RASSF1A might shift the balance of RAS activity towards a growth-promoting effect.
Class Human Diseases; Cancer: specific typesBRITE hierarchy
Pathway map Ortholog table Network Element N00007 EML4-ALK fusion kinase to RAS-ERK signaling pathway
N00008 RET fusion kinase to RAS-ERK signaling pathway
N00012 Mutation-activated KRAS/NRAS to ERK signaling pathway
N00014 Mutation-activated EGFR to RAS-ERK signaling pathway
N00022 ERBB2-overexpression to RAS-ERK signaling pathway
N00024 Mutation-activated EGFR to PLCG-ERK signaling pathway
N00025 EML4-ALK fusion kinase to PLCG-ERK signaling pathway
N00032 Mutation-activated KRAS/NRAS to PI3K signaling pathway
N00036 Mutation-activated EGFR to PI3K signaling pathway
N00041 EGFR-overexpression to RAS-ERK signaling pathway
N00047 EML4-ALK fusion kinase to PI3K signaling pathway
N00070 Mutation-inactivated p16(INK4a) to p16-cell cycle G1/S
N00097 Loss of RASSF1 to RAS-RASSF1 signaling pathway
N00105 EML4-ALK fusion kinase to Jak-STAT signaling pathway
N00115 Mutation-inactivated TP53 to transcription
N01062 Mutation-activated MET to RAS-ERK signaling pathway
N01063 Mutation-activated MET to PI3K signaling pathway
Disease H00014 Non-small cell lung cancer
Drug D01977 Gefitinib (JP18/USAN/INN)
D04023 Erlotinib hydrochloride (JAN/USAN)
D09731 Crizotinib (JAN/USAN/INN)
D09733 Afatinib dimaleate (USAN)
D10450 Alectinib hydrochloride (JAN)
D10551 Ceritinib (JAN/USAN/INN)
D10766 Osimertinib mesylate (USAN)
D10891 Capmatinib hydrochloride (USAN)
D11012 Lorlatinib (JAN/USAN/INN)
D11073 Tepotinib hydrochloride (USAN)
D11713 Selpercatinib (JAN/USAN/INN)
D11969 Mobocertinib succinate (JAN)
D12705 Gumarontinib hydrate (JAN)
Organism Homo sapiens (human) [GN:
hsa ]
Gene 5915 RARB; retinoic acid receptor beta [KO:K08528 ]
1029 CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621 ]
5925 RB1; RB transcriptional corepressor 1 [KO:K06618 ]
3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827 ]
11186 RASSF1; Ras association domain family member 1 [KO:K09850 ]
83593 RASSF5; Ras association domain family member 5 [KO:K08015 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
572 BAD; BCL2 associated agonist of cell death [KO:K02158 ]
7039 TGFA; transforming growth factor alpha [KO:K08774 ]
2885 GRB2; growth factor receptor bound protein 2 [KO:K04364 ]
6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099 ]
6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099 ]
3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833 ]
4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828 ]
1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625 ]
1647 GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402 ]
4616 GADD45B; growth arrest and DNA damage inducible beta [KO:K04402 ]
10912 GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402 ]
581 BAX; BCL2 associated X, apoptosis regulator [KO:K02159 ]
578 BAK1; BCL2 antagonist/killer 1 [KO:K14021 ]
1643 DDB2; damage specific DNA binding protein 2 [KO:K10140 ]
6774 STAT3; signal transducer and activator of transcription 3 [KO:K04692 ]
6776 STAT5A; signal transducer and activator of transcription 5A [KO:K11223 ]
6777 STAT5B; signal transducer and activator of transcription 5B [KO:K11224 ]
Compound C01245 D-myo-Inositol 1,4,5-trisphosphate
C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Osada H, Takahashi T.
Title Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer.
Journal Reference Authors Yokota J, Nishioka M, Tani M, Kohno T.
Title Genetic alterations responsible for metastatic phenotypes of lung cancer cells.
Journal Reference Authors Aviel-Ronen S, Blackhall FH, Shepherd FA, Tsao MS.
Title K-ras mutations in non-small-cell lung carcinoma: a review.
Journal Reference Authors Pfeifer GP, Dammann R.
Title Methylation of the tumor suppressor gene RASSF1A in human tumors.
Journal Reference Authors Altucci L, Gronemeyer H.
Title The promise of retinoids to fight against cancer.
Journal Reference Authors Virmani AK, Rathi A, Zochbauer-Muller S, Sacchi N, Fukuyama Y, Bryant D, Maitra A, Heda S, Fong KM, Thunnissen F, Minna JD, Gazdar AF.
Title Promoter methylation and silencing of the retinoic acid receptor-beta gene in lung carcinomas.
Journal Reference Authors Hirsch FR, Scagliotti GV, Langer CJ, Varella-Garcia M, Franklin WA.
Title Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies.
Journal Reference Authors Panani AD, Roussos C.
Title Cytogenetic and molecular aspects of lung cancer.
Journal Reference Authors Mitsuuchi Y, Testa JR.
Title Cytogenetics and molecular genetics of lung cancer.
Journal Reference Authors Breuer RH, Postmus PE, Smit EF.
Title Molecular pathology of non-small-cell lung cancer.
Journal Reference Authors Piyathilake CJ, Frost AR, Manne U, Weiss H, Bell WC, Heimburger DC, Grizzle WE.
Title Differential expression of growth factors in squamous cell carcinoma and precancerous lesions of the lung.
Journal Clin Cancer Res 8:734-44 (2002)
Reference Authors Awaya H, Takeshima Y, Furonaka O, Kohno N, Inai K.
Title Gene amplification and protein expression of EGFR and HER2 by chromogenic in situ hybridisation and immunohistochemistry in atypical adenomatous hyperplasia and adenocarcinoma of the lung.
Journal Reference Authors Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H
Title Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
Journal Reference Authors Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Hamada T, Haruta H, Watanabe H, Kurashina K, Hatanaka H, Ueno T, Takada S, Yamashita Y, Sugiyama Y, Ishikawa Y, Mano H
Title Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
Journal Reference Authors Janne PA, Gray N, Settleman J
Title Factors underlying sensitivity of cancers to small-molecule kinase inhibitors.
Journal Reference Authors Roskoski R Jr
Title Anaplastic lymphoma kinase (ALK): structure, oncogenic activation, and pharmacological inhibition.
Journal Reference Authors Reungwetwattana T, Weroha SJ, Molina JR
Title Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC).
Journal Reference Authors Popat S, Gonzalez D, Min T, Swansbury J, Dainton M, Croud JG, Rice AJ, Nicholson AG
Title ALK translocation is associated with ALK immunoreactivity and extensive signet-ring morphology in primary lung adenocarcinoma.
Journal Reference Authors Yoshida A, Tsuta K, Nakamura H, Kohno T, Takahashi F, Asamura H, Sekine I, Fukayama M, Shibata T, Furuta K, Tsuda H
Title Comprehensive histologic analysis of ALK-rearranged lung carcinomas.
Journal Reference Authors Shaozhang Z, Xiaomei L, Aiping Z, Jianbo H, Xiangqun S, Qitao Y
Title Detection of EML4-ALK fusion genes in non-small cell lung cancer patients with clinical features associated with EGFR mutations.
Journal Reference Authors Toyooka S, Mitsudomi T, Soh J, Aokage K, Yamane M, Oto T, Kiura K, Miyoshi S
Title Molecular oncology of lung cancer.
Journal Reference Authors Koudelakova V, Kneblova M, Trojanec R, Drabek J, Hajduch M
Title Non-small cell lung cancer--genetic predictors.
Journal Reference Authors Takeuchi K
Title Discovery Stories of RET Fusions in Lung Cancer: A Mini-Review.
Journal Reference Authors Ferrara R, Auger N, Auclin E, Besse B
Title Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer.
Journal Reference Authors Santoro M, Moccia M, Federico G, Carlomagno F
Title RET Gene Fusions in Malignancies of the Thyroid and Other Tissues.
Journal Related KO pathway
