Details of the Drug Combination

General Information of Drug Combination (ID: DCOO2Y4)

• Drug Combination Name: SCH 727965 + Erlotinib
• Indication: Ewing sarcoma-peripheral primitive neuroectodermal tumour; Status: Investigative [1]
• Component Drugs:
  SCH 727965 (DMCJLD1): Small molecular drug
  Erlotinib (DMCMBHA): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: ES2
  Zero Interaction Potency (ZIP) Score: 17.67
  Bliss Independence Score: 14.92
  Loewe Additivity Score: 10.69
  LHighest Single Agent (HSA) Score: 15.69

Molecular Interaction Atlas of This Drug Combination

Indication(s) of SCH 727965

Disease Entry	ICD 11	Status	REF
Acute lymphoblastic leukaemia	2A85	Discontinued in Phase 3	[2]

SCH 727965 Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Cyclin-dependent kinase 9 (CDK9)	TT1LVF2	CDK9_HUMAN	Inhibitor	[5]
Cyclin-dependent kinase 1 (CDK1)	TTH6V3D	CDK1_HUMAN	Inhibitor	[5]
Cyclin-dependent kinase 2 (CDK2)	TT7HF4W	CDK2_HUMAN	Inhibitor	[5]

SCH 727965 Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Retinoblastoma-associated protein (RB1)	OTQJUJMZ	RB_HUMAN	Decreases Phosphorylation	[6]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[6]
Breast cancer type 1 susceptibility protein (BRCA1)	OT5BN6VH	BRCA1_HUMAN	Decreases Expression	[7]
Breast cancer type 2 susceptibility protein (BRCA2)	OTF1XSV1	BRCA2_HUMAN	Decreases Expression	[7]
DNA repair protein RAD51 homolog 1 (RAD51)	OTNVWGC1	RAD51_HUMAN	Decreases Expression	[7]
Fanconi anemia group D2 protein (FANCD2)	OTVEB5LF	FACD2_HUMAN	Decreases Expression	[7]
Cyclin-dependent kinase 12 (CDK12)	OTZUDGNU	CDK12_HUMAN	Decreases Activity	[7]

Indication(s) of Erlotinib

Disease Entry	ICD 11	Status	REF
Adrenal gland neoplasm	N.A.	Approved	[3]
Adult hepatocellular carcinoma	N.A.	Approved	[3]
Brain cancer	2A00	Approved	[3]
Esophageal disorder	N.A.	Approved	[3]
Lung cancer	2C25.0	Approved	[3]
Non-small-cell lung cancer	2C25.Y	Approved	[4]
Pancreatic adenocarcinoma	N.A.	Approved	[3]
Psoriasis	EA90	Approved	[3]
Salivary gland squamous cell carcinoma	N.A.	Approved	[3]
Pancreatic cancer	2C10	Phase 3	[4]
Colon cancer	2B90.Z	Phase 2	[4]
Ependymoma	2A00.0Y	Investigative	[3]
Neoplastic meningitis	N.A.	Investigative	[3]
Neuroblastoma	2D11.2	Investigative	[3]

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	[8]

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	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]

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	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]

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	[13]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Breast and ovarian cancer syndrome	DC06VGB	UWB1289	Investigative	[14]
Breast and ovarian cancer syndrome	DC93LHY	UWB1289+BRCA1	Investigative	[14]
Breast carcinoma	DCEDSJE	KPL1	Investigative	[14]
Breast carcinoma	DCUBHQ4	OCUBM	Investigative	[14]
Carcinoma	DCFGRDD	OV90	Investigative	[14]
Carcinoma	DCR1TJX	EFM192B	Investigative	[14]
Carcinoma	DCTVIH3	MDAMB436	Investigative	[14]
Colon adenocarcinoma	DCA0IUH	LOVO	Investigative	[14]
Invasive ductal carcinoma	DC17L6R	T-47D	Investigative	[14]
Rectal adenocarcinoma	DCKS52X	SW837	Investigative	[14]
Adenocarcinoma	DCBGK5Y	CAOV3	Investigative	[15]
Adenocarcinoma	DCVT3OI	OVCAR3	Investigative	[15]
Adenocarcinoma	DCK04LM	A427	Investigative	[15]
Adenocarcinoma	DCYLYV6	NCIH1650	Investigative	[15]
Adenocarcinoma	DC9TDN7	NCIH23	Investigative	[15]
Adenocarcinoma	DCVUDQ8	NCIH520	Investigative	[15]
Adenocarcinoma	DC7WFAI	COLO320DM	Investigative	[15]
Adenocarcinoma	DCLRN0Z	DLD1	Investigative	[15]
Adenocarcinoma	DC98ZPQ	HT29	Investigative	[15]
Adenocarcinoma	DCX2GQ8	SW-620	Investigative	[15]
Amelanotic melanoma	DC33XGD	A2058	Investigative	[15]
Germ cell tumour	DCAMBJA	PA1	Investigative	[15]
Malignant melanoma	DCZPDQ3	A375	Investigative	[15]
Malignant melanoma	DC36TQ7	HT144	Investigative	[15]
Malignant melanoma	DCHT28T	RPMI7951	Investigative	[15]
Malignant melanoma	DC2RR4R	SKMEL30	Investigative	[15]
Malignant melanoma	DC4J01B	UACC62	Investigative	[15]
Non small cell carcinoma	DC2M3XJ	SKMES1	Investigative	[15]
Ovarian endometrioid adenocarcinoma	DCGASXP	A2780	Investigative	[15]
Ovarian serous cystadenocarcinoma	DCGPPPC	SK-OV-3	Investigative	[15]
Prostate carcinoma	DCHQO4B	LNCAP	Investigative	[15]
Prostate carcinoma	DCHM9M2	VCAP	Investigative	[15]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 7379).
• [3] Erlotinib 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: 4920).
• [5] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [6] Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. doi: 10.1158/1535-7163.MCT-10-0324. Epub 2010 Jul 27.
• [7] CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer. Cell Rep. 2016 Nov 22;17(9):2367-2381. doi: 10.1016/j.celrep.2016.10.077.
• [8] Quantitative prediction of fold resistance for inhibitors of EGFR. Biochemistry. 2009 Sep 8;48(35):8435-48.
• [9] 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.
• [10] Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy. Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33.
• [11] 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.
• [12] Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706.
• [13] 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.
• [14] Biologically active neutrophil chemokine pattern in tonsillitis.Clin Exp Immunol. 2004 Mar;135(3):511-8. doi: 10.1111/j.1365-2249.2003.02390.x.
• [15] Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy.Hum Genet. 2018 Apr;137(4):293-303. doi: 10.1007/s00439-018-1882-3. Epub 2018 Apr 24.