ArticleMolecular pharmacology2008
Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression and decreased BAK activation and not by ERBB receptor kinase mutation.
Article in Molecular pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 69 citations in OpenAlex.
- Mechanisms of Resistance to Chemotherapy in Hypopharyngeal Carcinoma.Biomedicines · 2025Review
- BCL-2 protein family: attractive targets for cancer therapy.Apoptosis : an international journal on programmed cell death · 2023Review
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- Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem.Cancer drug resistance (Alhambra, Calif.) · 2020Review
- Synthesis of novel 10,11-methylenedioxy-camptothecin glycoside derivatives and investigation of their anti-tumor effectsRSC advances · 2019Article
- Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL.BMC cancer · 2018Article
- ERRF sensitizes ERBB2-positive breast cancer cells to lapatinib treatment likely by attenuating MCL1 and ERBB2 expression.Oncotarget · 2017Article
- Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
- A Combination of Two Receptor Tyrosine Kinase Inhibitors, Canertinib and PHA665752 Compromises Ovarian Cancer Cell Growth in 3D Cell Models.Oncology and therapy · 2016Article
- Selective expression of constitutively active pro-apoptotic protein BikDD gene in primary mammary tumors inhibits tumor growth and reduces tumor initiating cells.American journal of cancer research · 2015Article
- PP2A inhibition overcomes acquired resistance to HER2 targeted therapy.Molecular cancer · 2014Article
- In vitro Development of Chemotherapy and Targeted Therapy Drug-Resistant Cancer Cell Lines: A Practical Guide with Case Studies.Frontiers in oncology · 2014Article
- Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy.Cancer biology & therapy · 2013Article
- A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.Science signaling · 2013Article
- An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models.Breast cancer research : BCR · 2013Article
- Lapatinib and obatoclax kill breast cancer cells through reactive oxygen species-dependent endoplasmic reticulum stress.Molecular pharmacology · 2012Article
- MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition.Oncogene · 2012Article
- Die and let live: harnessing BikDD to combat breast cancer stem cells.Breast cancer research : BCR · 2012Article
- Lapatinib and obatoclax kill tumor cells through blockade of ERBB1/3/4 and through inhibition of BCL-XL and MCL-1.Molecular pharmacology · 2012Article
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
Abstract
We have defined some of the mechanisms by which the kinase inhibitor lapatinib kills HCT116 cells. Lapatinib inhibited radiation-induced activation of ERBB1/2, extracellular signal-regulated kinases 1/2, and AKT, and radiosensitized HCT116 cells. Prolonged incubation of HCT116 cells with lapatinib caused cell killing followed by outgrowth of lapatinib-adapted cells. Adapted cells were resistant to serum starvation-induced cell killing and were cross-resistant to multiple therapeutic drugs. Lapatinib was competent to inhibit basal and epidermal growth factor (EGF)-stimulated ERBB1 phosphorylation in adapted cells. Coexpression of dominant-negative ERBB1 and dominant-negative ERBB2 inhibited basal and EGF-stimulated ERBB1 and ERBB2 phosphorylation in parental and adapted cells. However, in neither parental nor adapted cells did expression of dominant-negative ERBB1 and dominant-negative ERBB2 recapitulate the cell death-promoting effects of lapatinib. Adapted cells had increased expression of MCL-1, decreased expression of BAX, and decreased activation of BAX and BAK. Overexpression of BCL-XL protected parental cells from lapatinib toxicity. Knockdown of MCL-1 expression enhanced lapatinib toxicity in adapted cells that was reverted by knockdown of BAK expression. Inhibition of caspase function modestly reduced lapatinib toxicity in parental cells, whereas knockdown of apoptosis-inducing factor expression suppressed lapatinib toxicity. Thus, in HCT116 cells, lapatinib adaptation can be mediated by altered expression of pro- and antiapoptotic proteins that maintain mitochondrial function.
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