Details of the Drug Combination

General Information of Drug Combination (ID: DC9DY4O)

• Drug Combination Name: Erlotinib + BIBW 2992
• Indication: Lung Cancer; Status: Phase 2 [1]
• Component Drugs:
  Erlotinib (DMCMBHA): Small molecular drug
  BIBW 2992 (DMTKD7Q): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Erlotinib

Disease Entry	ICD 11	Status	REF
Adrenal gland neoplasm	N.A.	Approved	[2]
Adult hepatocellular carcinoma	N.A.	Approved	[2]
Brain cancer	2A00	Approved	[2]
Esophageal disorder	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[3]
Pancreatic adenocarcinoma	N.A.	Approved	[2]
Psoriasis	EA90	Approved	[2]
Salivary gland squamous cell carcinoma	N.A.	Approved	[2]
Pancreatic cancer	2C10	Phase 3	[3]
Colon cancer	2B90.Z	Phase 2	[3]
Ependymoma	2A00.0Y	Investigative	[2]
Neoplastic meningitis	N.A.	Investigative	[2]
Neuroblastoma	2D11.2	Investigative	[2]

Erlotinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[5]

Erlotinib Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[7]

Erlotinib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[9]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]

Erlotinib Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Increases Response	[10]

Indication(s) of BIBW 2992

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[4]

BIBW 2992 Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[11]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[11]

BIBW 2992 Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[12]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]

BIBW 2992 Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Epidermal growth factor receptor (EGFR)	OTAPLO1S	EGFR_HUMAN	Decreases Activity	[13]
Inhibitor of nuclear factor kappa-B kinase subunit beta (IKBKB)	OT9RDS3H	IKKB_HUMAN	Decreases Expression	[14]
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[15]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Affects Localization	[16]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[17]
Calmodulin-1 (CALM2)	OTNYA92F	CALM1_HUMAN	Affects Response To Substance	[18]

References

• [1] ClinicalTrials.gov (NCT02625168) Afatinib vs Erlotinib as 2nd TKI After Failure to 1st TKI and Chemotherapy for Metastatic NSCLC
• [2] Erlotinib FDA Label
• [3] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4920).
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5667).
• [5] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [6] Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008 Aug;7(8):2280-7.
• [7] Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33.
• [8] In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202-9.
• [9] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [10] Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. doi: 10.1056/NEJMoa040938. Epub 2004 Apr 29.
• [11] Boehringer Ingelheim. Product Development Pipeline. June 2 2009.
• [12] Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-gp/ABCB1) transport afatinib and restrict its oral availability and brain accumulation. Pharmacol Res. 2017 Jun;120:43-50.
• [13] Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011 Mar 10;54(5):1347-55. doi: 10.1021/jm101396q. Epub 2011 Feb 15.
• [14] Irreversible EGFR inhibitor EKB-569 targets low-LET -radiation-triggered rel orchestration and potentiates cell death in squamous cell carcinoma. PLoS One. 2011;6(12):e29705. doi: 10.1371/journal.pone.0029705. Epub 2011 Dec 29.
• [15] Tyrosine phosphorylation of the scaffold protein IQGAP1 in the MET pathway alters function. J Biol Chem. 2020 Dec 25;295(52):18105-18121. doi: 10.1074/jbc.RA120.015891. Epub 2020 Oct 21.
• [16] Oncoprotein SET dynamically regulates cellular stress response through nucleocytoplasmic transport in breast cancer. Cell Biol Toxicol. 2023 Aug;39(4):1795-1814. doi: 10.1007/s10565-022-09784-4. Epub 2022 Dec 19.
• [17] YM155 as an inhibitor of cancer stemness simultaneously inhibits autophosphorylation of epidermal growth factor receptor and G9a-mediated stemness in lung cancer cells. PLoS One. 2017 Aug 7;12(8):e0182149. doi: 10.1371/journal.pone.0182149. eCollection 2017.
• [18] Knockdown of CALM2 increases the sensitivity to afatinib in HER2-amplified gastric cancer cells by regulating the Akt/FoxO3a/Puma axis. Toxicol In Vitro. 2023 Mar;87:105531. doi: 10.1016/j.tiv.2022.105531. Epub 2022 Nov 29.