Drug Information

Drug (ID: DG00216) and It's Reported Resistant Information

• Name: Rociletinib
• Synonyms: 1374640-70-6; AVL-301; CO1686; UNII-72AH61702G; CNX-419; CO-1686 (AVL-301); Rociletinib(AVL-301,CNX-419,CO-1686); 72AH61702G; N-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide; CO 1686; Rociletinib (CO-1686, AVL-301); Rociletinib [USAN:INN]; Tube721; Rociletinib (USAN/INN); Rociletinib (CO-1686); SCHEMBL4177736; GTPL7966; CHEMBL3545308; EX-A228; MolPort-035-395-816; C27H28F3N7O3; HMS3653G08; BDBM149404; BCP07085; AOB87314; ZINC98043800; s7284
• Indication:
  In total 1 Indication(s)
  Lung cancer [ICD-11: 2C25]; Phase 3; [1], [2], [3]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Lung cancer [ICD-11: 2C25]; [1]
• Target: Epidermal growth factor receptor (EGFR); EGFR_HUMAN; [2]
• Formula: C27H28F3N7O3
• IsoSMILES: CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)NC4=CC(=CC=C4)NC(=O)C=C)C(F)(F)F)OC
• InChI: 1S/C27H28F3N7O3/c1-4-24(39)32-18-6-5-7-19(14-18)33-25-21(27(28,29)30)16-31-26(35-25)34-22-9-8-20(15-23(22)40-3)37-12-10-36(11-13-37)17(2)38/h4-9,14-16H,1,10-13H2,2-3H3,(H,32,39)(H2,31,33,34,35)
• InChIKey: HUFOZJXAKZVRNJ-UHFFFAOYSA-N
• PubChem CID: 57335384
• TTD Drug ID: D0M4AV
• DrugBank ID: DB11907

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [1], [2], [3]

• Molecule Alteration: Missense mutation; p.T790M
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Blood-based tumor genotyping assay; Liquid Biopsies assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Key Molecule: Epidermal growth factor receptor (EGFR) [1], [3]

• Molecule Alteration: Missense mutation; p.L798I
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Blood-based tumor genotyping assay; Liquid Biopsies assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Key Molecule: Epidermal growth factor receptor (EGFR) [1], [3]

• Molecule Alteration: Missense mutation; p.C797S
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: PC9 cells; Lung; Homo sapiens (Human); CVCL_B260
• Experiment for Molecule Alteration: Blood-based tumor genotyping assay; Liquid Biopsies assay; Circulating-free DNA assay
• Experiment for Drug Resistance: Overall and disease-free assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [1], [3]

• Molecule Alteration: Structural variation; Copy number gain
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Next-generation sequencing analysis; Gene copy number analysis
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Molecule Alteration: Structural variation; Copy number gain
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET signaling pathway; Activation; hsa04150
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Circulating tumour DNA (ctDNA) analysis
• Experiment for Drug Resistance: Tissue biopsy assay; CT scan assay; Growth inhibition assay; Receptor tyrosine kinase array; FISH and immunoblot profiling assay
• Mechanism Description: Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses.

Key Molecule: Hepatocyte growth factor receptor (MET) [1]

• Molecule Alteration: Structural variation; Amplification
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Circulating tumour DNA (ctDNA) analysis
• Experiment for Drug Resistance: Tissue biopsy assay; CT scan assay
• Mechanism Description: Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses.

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [1]

• Molecule Alteration: Structural variation; Amplification
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Circulating tumour DNA (ctDNA) analysis
• Experiment for Drug Resistance: Tissue biopsy assay; CT scan assay
• Mechanism Description: Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses.

Key Molecule: Retinoblastoma-associated protein (RB1) [1]

• Molecule Alteration: Single nucleotide variants; .
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Circulating tumour DNA (ctDNA) analysis
• Experiment for Drug Resistance: Tissue biopsy assay; CT scan assay
• Mechanism Description: Rociletinib resistance recurrently involves MET, EGFR, PIk3CA, ERRB2, kRAS and RB1.

Key Molecule: PI3-kinase alpha (PIK3CA) [1], [3]

• Molecule Alteration: Missense mutation; p.E545K
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating tumour DNA analysis; Next-generation sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Key Molecule: PI3-kinase alpha (PIK3CA) [1], [3]

• Molecule Alteration: Missense mutation; p.E542K
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating tumour DNA analysis; Next-generation sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Key Molecule: GTPase KRas (KRAS) [1], [3]

• Molecule Alteration: Missense mutation; p.Q61H
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating tumour DNA analysis; Next-generation sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Key Molecule: GTPase KRas (KRAS) [1], [3]

• Molecule Alteration: Missense mutation; p.G12A
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating tumour DNA analysis; Next-generation sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

Key Molecule: GTPase KRas (KRAS) [1], [3]

• Molecule Alteration: Missense mutation; p.A146T
• Resistant Disease: Non-small cell lung cancer [ICD-11: 2C25.Y]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating tumour DNA analysis; Next-generation sequencing assay
• Experiment for Drug Resistance: Progression-free survival assay
• Mechanism Description: Similarly,resistance to the third-generation inhibitor rociletinib may not only be mediated by EGFR (L798I, C797S) mutations, but also by alterations of MET, PIk3CA, ERRB2, and kRAS, and by the negative selection of T790M-mutant subclones.

References

• Ref 1: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun. 2016 Jun 10;7:11815. doi: 10.1038/ncomms11815.
• Ref 2: Noninvasive monitoring of the genetic evolution of EGFR-mutant non-small-cell lung cancer by analyzing circulating tumor DNA during combination chemotherapy with gefitinib and pemetrexed or S-1. Onco Targets Ther. 2016 Aug 24;9:5287-95. doi: 10.2147/OTT.S105976. eCollection 2016.
• Ref 3: Tumor Evolution as a Therapeutic Target. Cancer Discov. 2017 Jul 20. doi: 10.1158/2159-8290.CD-17-0343. Online ahead of print.