Farnesyl transferase expression determines clinical response to the docetaxel‐lonafarnib combination in patients with advanced malignancies

Abstract

BACKGROUND: Lonafarnib (LNF) is a protein farnesyl transferase (FTase) inhibitor that has shown synergistic activity with taxanes in preclinical models and early stage clinical trials. Preclinical findings suggested tubulin acetylation and FTase expression levels may be important determinants of drug sensitivity that would help identify patient populations more likely to benefit from this regimen. This pilot study evaluated the biological effects of LNF and docetaxel (DTX) combination therapy in refractory solid tumors by comparing pretreatment and post-treatment tumor biopsies. METHODS: Patients with histologically confirmed locally advanced or metastatic solid malignancies refractory to standard therapies or with no effective therapies available were eligible. Patients were randomized to 1 of 4 dosing cohorts: 1) 30 mg/m 2 , 100 mg; 2) 36 mg/m 2 , 100 mg; 3) 30 mg/m 2 , 150 mg; or 4) 36 mg/m 2 , 150mg of DTX intrave-

BRCA1 regulates microtubule dynamics and taxane-induced apoptotic cell signaling

“…We have recently shown that knockdown of protein farnesyltransferase, which unlike BRCA1 binds microtubules, also resulted in enhanced microtubule dynamicity and taxane resistance. 58,59 Clinically, we have also found a correlation between lower expression of farnesyltransferase and lack of clinical response to taxane-based chemotherapy, 60 similar to the existing clinical studies with BRCA1. Although, the exact pathway that links BRCA1 with microtubule dynamics remains to be fully elucidated, we provide here an explanation that links loss of BRCA1 with taxane insensitivity via the lack of microtubule-dependent activation of caspase-8 by the induced-proximity model (Figure 5).…”

Targeting protein prenylation for cancer therapy

“…To this end, a strategy to predict clinical response to FTIs was recently developed by Raponi et al Following the analysis of gene expression profiles from patients with untreated AML, these authors found that a high ratio of expression of two genes, RAS guanyl releasing protein 1 ( RASGRP1 ), which encodes a RAS guanine nucleotide exchange factor (GEF) that activates RAS, and aprataxin ( APTX ), which encodes a protein involved in DNA excision repair, predicts a tipifarnib-positive response of patients with AML 25,26 . Moreover, in patients with advanced solid cancers, low mRNA levels of FNTB , but not FNTA , are associated with improved response to lonafarnib plus taxane and significantly better survival 103 . Similar studies are needed for other types of cancer.…”

Farnesyltransferase Inhibitor in Cancer Treatment

“…In addition, in many models the effect of SCH66336 was additive to the effect of cytotoxic agents such as vincristine and cytoxan (Shi et al, 1999). Docetaxel-SCH66336 combination therapy in refractory solid tumors was tolerated in all cohorts with the exception of a 28% incidence of diarrhea (Kauh et al, 2011). Coadministration of continuous and intermittent SCH66336 enhanced the antitumor activity of docetaxel in a panel of prostate cancer models (Liu et al, 2009).…”

“…This heterodimer has two distinct subunits denoted as and , having molecular weights of 48 kDa and 46 kDa respectively (Machida et al, 2011;Zhang & Casey, 1996). The X-ray crystal structure of FTase reveals that it has binding sites for both the CAAX peptide and the FDP (Kauh et al, 2011;Park et al, 1997;Wei et al, 2011). It has been shown that geranylgeranyltransferase can prenylate some of the substrates of FTase and vice versa.…”