Details of the Drug Combination

General Information of Drug Combination (ID: DCW8VJC)

• Drug Combination Name: Osimertinib + BIBW 2992
• Indication: Carcinoma, Non-Small-Cell Lung; Status: Phase 1 [1]
• Component Drugs:
  Osimertinib (DMRJLAT): Small molecular drug
  BIBW 2992 (DMTKD7Q): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Osimertinib

Disease Entry	ICD 11	Status	REF
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Melanoma	2C30	Phase 3	[3]

Osimertinib 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	[7]

Osimertinib Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[8]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[6]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[9]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[9]

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	[10]
Epidermal growth factor receptor (EGFR)	TTGKNB4	EGFR_HUMAN	Inhibitor	[10]

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	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[11]

BIBW 2992 Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Ras GTPase-activating-like protein IQGAP1 (IQGAP1)	OTZRWTGA	IQGA1_HUMAN	Decreases Phosphorylation	[12]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Affects Localization	[13]
POU domain, class 5, transcription factor 1 (POU5F1)	OTDHHN7O	PO5F1_HUMAN	Decreases Expression	[14]

References

• [1] ClinicalTrials.gov (NCT03370770) Afatinib Osimertinib Sequencing NIS
• [2] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [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: 7719).
• [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] In vitro inhibition of human UDP-glucuronosyltransferase (UGT) 1A1 by osimertinib, and prediction of in vivo drug-drug interactions. Toxicol Lett. 2021 Sep 15;348:10-17. doi: 10.1016/j.toxlet.2021.05.004. Epub 2021 May 24.
• [6] Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene. 2019 Jan;38(5):656-670. doi: 10.1038/s41388-018-0482-y. Epub 2018 Aug 31.
• [7] AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61.
• [8] Dihydromyricetin suppresses tumor growth via downregulation of the EGFR/Akt/survivin signaling pathway. J Biochem Mol Toxicol. 2023 Jun;37(6):e23328. doi: 10.1002/jbt.23328. Epub 2023 Feb 19.
• [9] Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways. Biochem Pharmacol. 2022 Jan;195:114864. doi: 10.1016/j.bcp.2021.114864. Epub 2021 Nov 30.
• [10] Boehringer Ingelheim. Product Development Pipeline. June 2 2009.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.