Molecule Information

General Information of the Molecule (ID: Mol04126)

• Name: Myeloid cell leukemia 1 (Mcl-1) ,Homo sapiens
• Synonyms: Bcl-2-like protein 3; Bcl-2-related protein EAT/mcl1; mcl1/EAT
• Molecule Type: Protein
• Gene Name: MCL1
• Gene ID: 4170
• Location: chr1:150560895-150579738[-]
• Sequence:
  MFGLKRNAVIGLNLYCGGAGLGAGSGGATRPGGRLLATEKEASARREIGGGEAGAVIGGS
  AGASPPSTLTPDSRRVARPPPIGAEVPDVTATPARLLFFAPTRRAAPLEEMEAPAADAIM
  SPEEELDGYEPEPLGKRPAVLPLLELVGESGNNTSTDGSLPSTPPPAEEEEDELYRQSLE
  IISRYLREQATGAKDTKPMGRSGATSRKALETLRRVGDGVQRNHETAFQGMLRKLDIKNE
  DDVKSLSRVMIHVFSDGVTNWGRIVTLISFGAFVAKHLKTINQESCIEPLAESITDVLVR
  TKRDWLVKQRGWDGFVEFFHVEDLEGGIRNVLLAFAGVAGVGAGLAYLIR
• 3D-structure: PDB ID: 8G3S; Classification: Apoptosis; Method: X-ray diffraction; Resolution: 1.40 Å
• Function: Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis. .
• Uniprot ID: MCL1_HUMAN
• Ensembl ID: ENSG00000143384
• HGNC ID: HGNC:6943

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Oesophagus adenocarcinoma [ICD-11: 2B70.0] [2]

• Resistant Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KYSE-70-R cells; esophageal; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Combination index assay
• Mechanism Description: We consistently observed an increase in the expression of Mcl-1 in cells exposed to both short and long-term treatment with cisplatin, a drug commonly used in esophageal cancer therapy. Functional analysis showed that Mcl-1 regulates esophageal cancer cell response to cisplatin treatment. Notably, this upregulation of Mcl-1 was not dependent on eukaryotic initiation factor 4E (eIF4E). Instead, it was associated with increased stability due to the activation of Akt. Capivasertib, a potent pan-Akt kinase drug, significantly decreased Mcl-1 level via inhibiting Akt signaling pathway in chemo-resistant cells. In addition, capivasertib not only decreased the viability of chemo-resistant esophageal cancer cells but also synergistically enhanced the effects of cisplatin.

Ibrutinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [3]

• Metabolic Type: Redox metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Ibrutinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CD40L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY18 cells; Blood; Homo sapiens (Human); CVCL_1880
• In Vitro Model: OCI-LY19 cells; Bone marrow; Homo sapiens (Human); CVCL_1878
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: U-2932 cells; Blood; Homo sapiens (Human); CVCL_1896
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Treatment with AZD5991 restricted growth of DLBCL cells independent of cell of origin and overcame ibrutinib resistance in MCL cells. Mcl-1 inhibition led to mitochondrial dysfunction as manifested by mitochondrial membrane depolarization, decreased mitochondrial mass, and induction of mitophagy. This was accompanied by impairment of oxidative phosphorylation. TP53 and BAX were essential for sensitivity to Mcl-1, and oxidative phosphorylation was implicated in resistance to Mcl-1 inhibition.

Clinical Trial Drug(s) 1 drug(s) in total

Capivasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Oesophagus adenocarcinoma [ICD-11: 2B70.0] [2]

• Sensitive Disease: Oesophagus adenocarcinoma [ICD-11: 2B70.0]
• Sensitive Drug: Capivasertib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KYSE-70-R cells; esophageal; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Combination index assay
• Mechanism Description: We consistently observed an increase in the expression of Mcl-1 in cells exposed to both short and long-term treatment with cisplatin, a drug commonly used in esophageal cancer therapy. Functional analysis showed that Mcl-1 regulates esophageal cancer cell response to cisplatin treatment. Notably, this upregulation of Mcl-1 was not dependent on eukaryotic initiation factor 4E (eIF4E). Instead, it was associated with increased stability due to the activation of Akt. Capivasertib, a potent pan-Akt kinase drug, significantly decreased Mcl-1 level via inhibiting Akt signaling pathway in chemo-resistant cells. In addition, capivasertib not only decreased the viability of chemo-resistant esophageal cancer cells but also synergistically enhanced the effects of cisplatin.

Preclinical Drug(s) 1 drug(s) in total

A-1155463

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [ICD-11: 2B91.1] [4]

• Resistant Disease: Colorectal cancer [ICD-11: 2B91.1]
• Resistant Drug: A-1155463
• Molecule Alteration: Expression; H3K27Me3
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FGFR4 signalling pathway; Regulation; N.A.
• In Vitro Model: Co01 cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Viability assay
• Mechanism Description: We identify a rescue response that is activated upon BCL-XL inhibition and leads to rapid?FGF2?secretion and subsequent FGFR4-mediated post-translational stabilization of MCL-1. FGFR4 inhibition prevents MCL-1 upregulation and thereby sensitizes CSCs to BCL-XL inhibition. Altogether, our findings suggest a cell transferable induction of a FGF2/FGFR4 rescue response in CRC that is induced upon BCL-XL inhibition and leads to MCL-1 upregulation.

Investigative Drug(s) 1 drug(s) in total

Imiquimod

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [5]

• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Imiquimod
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: TLR7 signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: PI3K signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: JAK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: PI3K/Akt signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: JAK/STAT3 signaling pathway; Activation; hsa04630
• In Vitro Model: BCC/KMC-1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: AGS cells; Gastric; Homo sapiens (Human); CVCL_0139
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Cellular assay; Mitochondrial ROS assay; Lipid ROS assay; Cell viability assay; DNA content assay; Mitochondrial oxygen consumption assay
• Mechanism Description: In this study, we demonstrated that Mcl-1 overexpression induced resistance to IMQ-induced apoptosis and reduced both IMQ-induced ROS generation and oxidative stress in cancer cells. Mcl-1 overexpression maintained mitochondrial function and integrity and prevented mitophagy in IMQ-treated cancer cells. Furthermore, IL-6 protected against IMQ-induced apoptosis by increasing Mcl-1 expression and attenuating IMQ-induced mitochondrial fragmentation. Mcl-1 overexpression ameliorates IMQ-induced ROS generation and mitochondrial fragmentation, thereby increasing mitochondrial stability and ultimately attenuating IMQ-induced cell death. Investigating the roles of Mcl-1 in mitochondria is a potential strategy for cancer therapy development.

References

• Ref 1: Initial AXL and MCL-1 inhibition contributes to abolishing lazertinib tolerance in EGFR-mutant lung cancer cells. Cancer Sci. 2024 Oct;115(10):3333-3345.
• Ref 2: Capivasertib reverses chemotherapy-induced esophageal cancer resistance via inhibiting Akt-associated Mcl-1 upregulation. Heliyon. 2024 Jun 25;10(13):e33567.
• Ref 3: Pharmacologic Targeting of Mcl-1 Induces Mitochondrial Dysfunction and Apoptosis in B-Cell Lymphoma Cells in a TP53- and BAX-Dependent Manner. Clin Cancer Res. 2021 Sep 1;27(17):4910-4922.
• Ref 4: BCL-XL inhibition induces an FGFR4-mediated rescue response in colorectal cancer. Cell Rep. 2022 Feb 15;38(7):110374.
• Ref 5: The Protective Effects of Mcl-1 on Mitochondrial Damage and Oxidative Stress in Imiquimod-Induced Cancer Cell Death. Cancers (Basel). 2024 Sep 2;16(17):3060.