Details of the Drug Combination

General Information of Drug Combination (ID: DCWF9PL)

• Drug Combination Name: Buparlisib + Oxaliplatin
• Indication: Advanced Solid Tumors; Status: Phase 1 [1]
• Component Drugs:
  Buparlisib (DM1WEHC): Small molecular drug
  Oxaliplatin (DMQNWRD): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Buparlisib

Disease Entry	ICD 11	Status	REF
Breast cancer	2C60-2C65	Phase 3	[2]

Buparlisib Interacts with 4 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
PI3-kinase beta (PIK3CB)	TTTHBCA	PK3CB_HUMAN	Inhibitor	[6]
PI3-kinase delta (PIK3CD)	TTGBPJE	PK3CD_HUMAN	Inhibitor	[6]
PI3-kinase alpha (PIK3CA)	TTEUNMR	PK3CA_HUMAN	Inhibitor	[6]
PI3-kinase gamma (PIK3CG)	TTHBTOP	PK3CG_HUMAN	Inhibitor	[6]

Buparlisib Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Telomerase reverse transcriptase (TERT)	OT085VVA	TERT_HUMAN	Decreases Expression	[5]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[7]
Forkhead box protein O3 (FOXO3)	OTHXQG4P	FOXO3_HUMAN	Increases Expression	[7]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[8]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[5]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[8]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Increases Phosphorylation	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[5]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[8]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Phosphorylation	[9]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[5]
Baculoviral IAP repeat-containing protein 3 (BIRC3)	OT3E95KB	BIRC3_HUMAN	Decreases Expression	[5]
Baculoviral IAP repeat-containing protein 2 (BIRC2)	OTFXFREP	BIRC2_HUMAN	Decreases Expression	[5]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[5]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Decreases Expression	[5]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Response To Substance	[10]

Indication(s) of Oxaliplatin

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[3]
Appendiceal neoplasm	N.A.	Approved	[3]
Cholangiocarcinoma	2C12.10	Approved	[3]
Colon adenocarcinoma	N.A.	Approved	[3]
Colorectal cancer	2B91.Z	Approved	[4]
Colorectal carcinoma	N.A.	Approved	[3]
Endocrine gland neoplasm	N.A.	Approved	[3]
Gallbladder carcinoma	N.A.	Approved	[3]
Metastasis from malignant tumor of colon	N.A.	Approved	[3]
Nasopharyngeal carcinoma	2B6B	Approved	[3]
Peritoneal neoplasm	N.A.	Approved	[3]
Rectal adenocarcinoma	2B92	Approved	[3]
Rectal neoplasm	N.A.	Approved	[3]
Rectum mucinous adenocarcinoma	N.A.	Approved	[3]
Colon cancer	2B90.Z	Investigative	[3]
Gastric cancer	2B72	Investigative	[3]

Oxaliplatin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[11]

Oxaliplatin Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[12]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[13]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[14]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[15]
High affinity copper uptake protein 1 (SLC31A1)	DTP8L4F	COPT1_HUMAN	Substrate	[16]

Oxaliplatin Interacts with 12 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[17]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[17]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[17]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[17]
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[18]
Glutathione S-transferase theta-1 (GSTT1)	DE3PKUG	GSTT1_HUMAN	Metabolism	[18]
Metallothionein-1A (MT1A)	DE5ME8A	MT1A_HUMAN	Metabolism	[18]
Metallothionein-2A (MT2A)	DEFKGT7	MT2_HUMAN	Metabolism	[18]
Myeloperoxidase (MPO)	DEA3U9Y	PERM_HUMAN	Metabolism	[18]
Quinone reductase 1 (NQO1)	DENP5RY	NQO1_HUMAN	Metabolism	[18]
Superoxide dismutase 1 (SOD1)	DEUTDON	SODC_HUMAN	Metabolism	[18]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[18]

Oxaliplatin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Protachykinin-1 (TAC1)	OTM842YW	TKN1_HUMAN	Increases ADR	[19]

References

• [1] ClinicalTrials.gov (NCT01571024) BKM120 + mFOLFOX6 in Advanced Solid Tumors With Expansion Cohort Pancreatic Cancer
• [2] 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: 7878).
• [3] Oxaliplatin FDA Label
• [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: 7433).
• [5] Inhibition of PI3K signaling pathway enhances the chemosensitivity of APL cells to ATO: Proposing novel therapeutic potential for BKM120. Eur J Pharmacol. 2018 Dec 15;841:10-18. doi: 10.1016/j.ejphar.2018.10.007. Epub 2018 Oct 11.
• [6] Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009 Aug;8(8):627-44.
• [7] Inhibition of PI3K pathway using BKM120 intensified the chemo-sensitivity of breast cancer cells to arsenic trioxide (ATO). Int J Biochem Cell Biol. 2019 Nov;116:105615. doi: 10.1016/j.biocel.2019.105615. Epub 2019 Sep 17.
• [8] Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer. Cancer Lett. 2014 Jun 1;347(2):204-11. doi: 10.1016/j.canlet.2014.02.018. Epub 2014 Feb 24.
• [9] The dual PI3K/mTOR inhibitor NVP-BEZ235 and chloroquine synergize to trigger apoptosis via mitochondrial-lysosomal cross-talk. Int J Cancer. 2013 Jun 1;132(11):2682-93. doi: 10.1002/ijc.27935. Epub 2012 Dec 4.
• [10] Characterization of the mechanism of action of the pan class I PI3K inhibitor NVP-BKM120 across a broad range of concentrations. Mol Cancer Ther. 2012 Aug;11(8):1747-57. doi: 10.1158/1535-7163.MCT-11-1021. Epub 2012 May 31.
• [11] Structures of oxaliplatin-oligonucleotide adducts from DNA.J Mass Spectrom.2012 Oct;47(10):1282-93.
• [12] Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
• [13] Effect of ABCG2 on cytotoxicity of platinum drugs: interference of EGFP. Toxicol In Vitro. 2008 Dec;22(8):1846-52.
• [14] Relevance of copper transporter 1 and organic cation transporters 1-3 for oxaliplatin uptake and drug resistance in colorectal cancer cells. Metallomics. 2018 Mar 1;10(3):414-425.
• [15] Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006 Sep 1;66(17):8847-57.
• [16] Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol. 2005 Jan;53(1):13-23.
• [17] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [18] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA150642262)
• [19] Polymorphic markers associated with severe oxaliplatin-induced, chronic peripheral neuropathy in colon cancer patients. Cancer. 2012 Jun 1;118(11):2828-36. doi: 10.1002/cncr.26614. Epub 2011 Oct 21.