Genomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR

Figures & data

Figure 1 Frequency of selected molecular alterations in lung adenocarcinomas and squamous cell carcinomas.

Notes: The frequency of selected molecular alterations as reported in The Cancer Genome Atlas for (A) lung adenocarcinomas (230 samples) and (B) squamous cell carcinomas (178 samples). Red represents gene amplification, blue represents homozygous deletion, green represents mutation, and a black triangle represents a gene fusion. This figure is adapted from an OncoPrint figure generated at http://www.cbioportal.org.¹²²
Abbreviations: TP53, tumor protein p53; EGFR, epidermal growth factor receptor; STK11, serine/threonine kinase 11; ALK, anaplastic lymphoma receptor tyrosine kinase; RET, ret proto-oncogene; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; PTEN, phosphatase and tensin homolog; CDKN2A, cyclin-dependent kinase inhibitor 2A; FGFR1, fibroblast growth factor receptor 1.

Table 1 Selected clinical trials for EGFR-resistant NSCLC

Drug	Target(s)	Phase	Identifier*
AZD9291	EGFR T790M	I/II	NCT01802632
PF-02341066	MET inhibitor
PF-00299804	PAN-HER inhibitor	I	NCT01121575
BIBW 2992	EGFR and ERBB2	II	NCT01542437
Bevacizumab	VEGF	II	NCT02139579
Selumetinib	EGFR T790M	I/II	NCT02025114
ASP8273	EGFR T790M	I/II	NCT02192697
MSC2156119J	MET	I/II	NCT01982955
ARQ 197	MET	II	NCT01580735
Arsenic trioxide	Apoptotic pathway	I	NCT02066870
AUY922	Hsp90	I/II	NCT01259089
Everolimus	PI3K/AKT/MTOR		NCT00124280
Vorinostat-Iressa	HDAC	I	NCT02151721

Note:

* Identifier from ClinicalTrials.gov.

Abbreviations: EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; VEGF, vascular endothelial growth factor; Hsp90, heat shock protein 90; PI3K, phosphatidylinositol 3-kinases; MTOR, mammalian target of rapamycin; HDAC, histone deacetylase inhibitor.

Table 2 Selected clinical trials using ALK inhibitors

Therapeutic	Target(s)	Phase	Identifier*
Alectinib (CH5424802)	ALK	III	NCT02075840
AP26113	ALK/EGFR	I/II	NCT01449461
TSR-001	ALK/TRK	I/IIa	NCT02048488
X-396	ALK	I	NCT01625234
CEP-37440	ALK/FAK	I	NCT01922752
Ganetespib (STA-9090)	Hsp90	I/II	NCT01579994
		III	NCT01798485
AP36113	ALK/EGFR	I/II	NCT01449461
AUY992	Hsp90	II	NCT01752400
AT13387	Hsp90	I/II	NCT01712217
DS-2248	Hsp90	I	NCT01288430

Note:

* Identifier from ClinicalTrials.gov.

Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; EGFR, epidermal growth factor receptor; Hsp90, heat shock protein 90.

Table 3 Selected clinical trials for FGFR1 in SCC

Drug	Target(s)	Phase	Identifier*
Nintedanib (BIBF 1120)	VEGFR, PDGFR, and FGFR	I/II	NCT01346540
		II	NCT01948141
Ponatinib	Multitargeting tyrosine kinase	II/III	NCT01761747
		II	NCT01935336
AZD4547	FGFR1–4, VEGF4	I	NCT00979134
		II	NCT01795768
		II/III	NCT02154490
		I/II	NCT01824901

Note:

* Identifier from ClinicalTrials.gov.

Abbreviations: FGFR1, fibroblast growth factor receptor I; SCC, squamous cell carcinoma; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor.

Table 4 Selected clinical trials for PIK3CA in SCC

Drug	Target(s)	Phase	Identifier*
Buparlisib (BKM120)	Pan-PI3K	II	NCT01297491
		I/II	NCT01820325
		II	NCT01911325
		II	NCT01833169
PX-866	Pan-PI3K	I/II	NCT01204099
BYL719	Alpha class I PI3K	I	NCT01219699
		Ib/II	NCT01602315
		Ib	NCT01449058

Note:

* Identifier from ClinicalTrials.gov.

Abbreviations: PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; SCC, squamous cell carcinoma; PI3K, phosphatidylinositol 3-kinases.

Table 5 Selected clinical trials for mtKRAS tumors

Drug	Target(s)	Phase	Identifier*
Bortezomib	Proteasome	II	NCT01833143
VS-6063	FAK	II	NCT01951690
AZD6244	MEK	II	NCT01306045
GI-4000	mtKRAS	II	NCT00655161
IPI-504	Hsp90		NCT01427946
Everolimus	MTOR	I/II
MEK162	MEK	I	NCT01337765
BEZ235	PI3K/AKT
PD-0325901	MEK	I/II	NCT02022982
PALBOCICLIB	CDK4/6
MEK162	MEK	I/Ib	NCT01859026
Erlotinib	EGFR
Trametinib	MEK	Ib/II	NCT02079740
Navitoclax	BCL2/BCLXL
MEK162	MEK	I/Ib	NCT02185690
Carboplatin	DNA damage

Note:

* Identifier from ClinicalTrials.gov.

Abbreviations: mtKRAS, activating KRAS mutations; Hsp90, heat shock protein 90; MTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinases; CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor.

Table 6 Selected clinical trials targeting TP53

Drug	Target(s)	Tumor	Phase	Identifier*
rAd-p53	TP53	NSCLC	II	NCT01574729
Ad5CMV-p53	TP53	NSCLC	I	NCT00004225
Mutant p53 peptide vaccine	mt-TP53	NSCLC	II	NCT00019929
AZD-1775	WEE1	Ovary	II	NCT01164995

Note:

* Identifier from ClinicalTrials.gov.

Abbreviations: TP53, tumor protein p53; NSCLC, non-small cell lung cancer.

Figure 2 Molecular alterations in lung adenocarcinomas with targeted therapeutic opportunities.

Abbreviations: RET, ret proto-oncogene; EGFR, epidermal growth factor receptor; mABs, monoclonal antibodies; TKI, tyrosine kinase inhibitor; ALK, anaplastic lymphoma receptor tyrosine kinase; KRAS, Kirsten rat sarcoma viral oncogene homolog; PI3K, phosphatidylinositol 3-kinases; LKB1, serine/threonine kinase 11; p53, tumor protein p53; Hsp90, heat shock protein 90; MTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase.

Figure 3 Molecular alterations in squamous cell lung carcinomas with targeted therapeutic opportunities.

Abbreviations: FGFR, fibroblast growth factor receptor; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; PIK3, phosphatidylinositol 3-kinases; PTEN, phosphatase and tensin homolog; p53, tumor protein p53; Hsp90, heat shock protein 90; MTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase.

Table S1 HUGO approved name and symbol

HUGO approved name	Symbol	Other
V-akt murine thymoma viral oncogene homolog 3	AKT3
Anaplastic lymphoma receptor tyrosine kinase	ALK
AT rich interactive domain 1A (SWI-like)	ARID1A
ATM serine/threonine kinase	ATM
BCL2-like 1	BCL2L1	BCLXL
BCL2-like 11 (apoptosis facilitator)	BCL2L11	BIM
B-Raf proto-oncogene, serine/threonine kinase	BRAF
Coiled–coil domain containing 6	CCDC6
Cyclin-dependent kinase inhibitor 2A	CDKN2A
Checkpoint kinase 1	CHEK1
Checkpoint kinase 2	CHEK2
Cytotoxic T-lymphocyte-associated protein 4	CTLA4
Deoxythymidylate kinase (thymidylate kinase)	DTYMK
Epidermal growth factor receptor	EGFR	ERBB1
Echinoderm microtubule associated protein like 4	EML4
V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2	ERBB2	HER2
Mitogen-activated protein kinase 3	MAPK3	ERK1
Mitogen-activated protein kinase 1	MAPK1	ERK2
Fibroblast growth factor receptor 1	FGFR1
Hepatocyte growth factor	HGF
Major histocompatibility complex, class I, A	HLA-A
Harvey rat sarcoma viral oncogene homolog	HRAS
Heat shock protein 90kDa alpha (cytosolic), class A member 1	HSP90AA1
Insulin-like growth factor 1 receptor	IGFR1
Kelch-like ECH-associated protein 1	KEAP1
Kinesin family member 5B	KIF5B
Kirsten rat sarcoma viral oncogene homolog	KRAS
Mitogen-activated protein kinase kinase 1-7	MAP2K1-7	MEK
MET proto-oncogene, receptor tyrosine kinase	MET	HGFR
Lysine (K)-specific methyltransferase 2D	KMT2D
Nuclear receptor coactivator 4	NCOA4
Neurofibromin 1	NF1
Nuclear factor, erythroid 2-like 2	NFE2L2
Notch 1	NOTCH1
Neuroblastoma RAS viral (v-ras) oncogene homolog	NRAS
Programmed cell death 1	PDCD-1
Platelet-derived growth factor receptor, beta polypeptide	PDGFRB
CD274 molecule	CD274	PD-L1
Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha	PIK3CA
Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta/delta	PIK3CB/D
Phosphoinositide-3-kinase, regulatory subunit 1-3	PIK2R1-3
Polo-like kinase 1	PLK1
Phosphatase and tensin homolog	PTEN
Retinoblastoma 1	RB1
RNA binding motif protein 10	RBM10
Ret proto-oncogene	RET
Ras-like without CAAX 1	RIT1
ROS proto-oncogene 1, receptor tyrosine kinase	ROS1
SET domain containing 2	SETD2
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4	SMARCA4
Serine/threonine kinase 11	STK11	LKB1
TRK-fused gene	TFG
Tumor protein p53	TP53	P53
Tripartite motif containing 33	TRIM33
U2 small nuclear RNA auxiliary factor 1	U2AF1
Vascular endothelial growth factor A	VEGFA
C-fos induced growth factor (vascular endothelial growth factor D)	FIGF
Kinase insert domain receptor (a type III receptor tyrosine kinase)	KDR
WEE1 G2 checkpoint kinase	WEE1

Abbreviation: HUGO, Human Genome Organisation.

cbioportal.org [homepage on the Internet]cBioPortal for Cancer Genomics Available from: http://www.cbioportal.org/Accessed January 27, 2015

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