Resistance to HER2-directed antibodies and tyrosine kinase inhibitors

Garrett, Joan T.; Arteaga, Carlos L.

doi:10.4161/cbt.11.9.15045

Cited by 165 publications

(140 citation statements)

References 92 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…Selective inhibitors of RAF, such as PLX4032, have remarkable clinical activity in patients with mela nomas who carry mutated BRAF (112). However, as for other inhibitors of oncogenic kinases (113,114), response to PLX4032 is profound but often temporary, because of the loss of addiction and the onset of resistance (115). Moreover, the functional role of MAPKs in the heart itself presents a potential dilemma to any heart disease therapies targeting this pathway: the physiological role of RAS signaling should not be forgotten.…”

Section: Future Directions For Therapymentioning

confidence: 99%

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Sala

Gallo

Leo

et al. 2012

Mol Med

View full text Add to dashboard Cite

Section: Future Directions For Therapymentioning

confidence: 99%

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Sala

Gallo

Leo

et al. 2012

Mol Med

View full text Add to dashboard Cite

“…PI3 kinase-AKT-FOX1A) for example via loss of PTEN or by PIK3CA mutations. (Garrett and Arteaga, 2011). In the early days, the development of host antibodies against the therapeutic antibody could neutralise their activity upon repeat administration.…”

Section: Links Between Erb-b Signalling and Resistance To Therapymentioning

confidence: 99%

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

Eccles¹

2011

Int. J. Dev. Biol.

159

123

View full text Add to dashboard Cite

KEY WORDS: EGFR, c-Erb-B2, c-Erb-B3, c-Erb-B4, cancer The EGFR/ERB-B/HER familyThe epidermal growth factor receptor (EGFR) and its close relatives HER2/c-Erb-B2, Erb-B3 and Erb-B4 are type 1 transmembrane receptor tyrosine kinases (RTK) with key roles in embryonic development, tissue renewal/repair and cancer. A great deal has been learned about their structure, signalling pathways and aberrations linked to malignant transformation since the explosion of interest in this family in the 1980's. Early discoveriesregulated eyelid opening in mice, and as the binding partner for EGFR was found to have kinase activity when stimulated with ligands and to be capable of phosphorylating tyrosine residues on both itself and downstream targets. Even before EGFR was identiInt. J. Dev. Biol. 55: [685][686][687][688][689][690][691][692][693][694][695][696]

show abstract

“…Nevertheless, more than 80% of HER2-positive gastric tumors are resistant to systemic trastuzumab, while continuing to depend on the HER2 oncogene, suggesting that local antibody concentrations achieved with systemic therapy are insufficient for therapeutic efficacy (34,40). Indeed, low tumor penetration and rapid clearance of monoclonal antibodies when given intravenously are major obstacles (9,10), which cannot be overcome by increasing doses due to the risks associated with on-target, off-tumor toxicity as exemplified by the fatal cardiomyopathy seen in trastuzumab-treated patients (11,12).…”

Section: Discussionmentioning

confidence: 99%

Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer

Liikanen

Tähtinen

Guse

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with fulllength trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus, Ad5/3-D24-tras, coding for human trastuzumab antibody heavy-and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-D24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-D24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-D24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-D24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. Mol Cancer Ther; 15(9); 2259-69. Ó2016 AACR.

show abstract

Resistance to HER2-directed antibodies and tyrosine kinase inhibitors

Cited by 165 publications

References 92 publications

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer

Contact Info

Product

Resources

About