Latest research on Erlotinib

Erlotinib hydrochloride (trade name Tarceva, Genentech/OSIP, originally coded as OSI-774) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.

Latest findings

In both HCC827 and PC9 EGFR-mutant lung cancer cells, three of 14 BH3-domain containing proteins tested showed strongly reduced mRNA induction by Erlotinib in the presence of ectopic SOX2: BIM, BMF, and HRK (but not PUMA) (Figure 6A and Figure 6—figure supplement 1). [source]
Importantly, ChIP qPCR demonstrated significant enhancement of SOX2 binding with Erlotinib treatment at both peaks compared to untreated cells, suggesting that binding is functionally significant (Figure 6B, lower). [source]
Expression of all of the FOXO family members was detectable at baseline in HCC827 cells and Erlotinib treatment (8 hr) was associated with a 1.6–4.4-fold induction (Figure 7B), as well as with loss of the AKT-mediated inhibitory N-terminal Threonine phosphorylation of the FOXO proteins (Figure 7—figure supplement 2A). [source]
Virtually all EGFR-mutant lung cancer cell lines established from patients who have not been treated with Erlotinib are highly sensitive to this drug, although a few cells lines appear to be intrinsically resistant. [source]
The HCC2935 human lung cancer cell line is remarkable for harboring a characteristic oncogene-addicting EGFR mutation (exon 19 deletion) yet having unexplained resistance to Erlotinib (Figure 8A), including absence of the common T790M gatekeeper mutation within EGFR and no amplification of the MET bypass signaling pathway (Zheng et al., 2011). [source]
To test whether increased SOX2 contributes to decreased Erlotinib sensitivity in HCC2935 cells, we knocked down SOX2 using siRNA. [source]
Thus, increased baseline SOX2 contributes to Erlotinib resistance in these EGFR-mutant cells. [source]
Other pathways that have been implicated in SOX2 regulation in the developing lung, including FGF10, WNT/beta-Catenin signaling, and TTF1 (Que et al., 2007; Gontan et al., 2008; Hashimoto et al., 2012), had relatively modest effects on its induction following Erlotinib treatment in EGFR-mutant cancer cells (Figure 7—figure supplement 4), pointing to FOXO6 as the dominant pathway in this model of oncogene-dependent signaling. [source]
We favor the latter model, given the absent coexpression of SOX2 with putative stem cell markers, the failure to enrich for SOX2 positive cells following repeated Erlotinib treatments, and the regeneration of heterogeneous SOX2 inducibility following single cell cloning experiments. [source]
Critically, the ability of siRNA targeting SOX2 to substantially decrease the number and rate at which resistant subclones of EGFR-mutant cells emerge following continuous Erlotinib treatment suggests that, despite its heterogeneous, transient, and stochastic expression, SOX2 contributes to the emergence of stably acquired resistance (Figure 5E). [source]