BHD-associated kidney cancers are thought to arise from somatic mutation of the remaining wild type allele of the BHD gene, FLCN, meaning that tumours are genetically distinct from surrounding tissue (Vocke et al., 2005). The phenomenon of synthetic lethality describes the situation where inhibiting a gene, by mutation or with a drug, is lethal to cancer cells with an existing genetic defect, but not in healthy tissue lacking this defect. Targeted therapies are an attractive area of research, as treatments that don’t effect healthy tissue are predicted to cause fewer side effects, and as such synthetic lethal targets have been found in BHD, VHL and HLRCC kidney cancers.
In 2011, Lu et al. showed that a number of drug compounds caused toxicity in FLCN-null, but not FLCN-expressing cell lines. While Lu et al. concentrated on the drug that proved the most toxic, mithramycin, a recent study has sought to characterise how the drug Paclitaxel – which was the second most potent drug found in the Lu et al. screen – stops the growth of FLCN-null cells (Zhang et al., 2013).
Firstly, the authors used two FLCN-null and FLCN-expressing isogenic cell lines, UOK-257 and ACHN, to confirm that Paclitaxel is more cytotoxic to FLCN-null cells than FLCN-expressing cells. In both cell lines, FLCN-null cells showed increased apoptosis in response to Paclitaxel, in a dose-dependent manner, as shown by TUNEL staining, greater DAPI staining and increased levels of cleaved Caspase 3.
Paclitaxel is also thought to effect autophagy in a cell-dependent manner (Liu et al., 2013, Veldhoen et al., 2013). Additionally, autophagy dysregulation is known to be a common feature in familial kidney cancers, and several studies have suggested FLCN may function in this process, as discussed in this previous blog post. Thus, the authors decided to investigate whether Paclitaxel had any effect on autophagy in FLCN-null cells and how this may modify cellular response to the drug.
Indeed, the authors showed that Paclitaxel specifically induces autophagy in FLCN-deficient cells, indicating that FLCN-null cells could develop some resistance to Paclitaxel by recycling unnecessary cellular components for energy. This effect seemed to be mediated by an increase in MEK-ERK signalling, as ERK inhibition reduced autophagy in these cells.
Furthermore, inhibiting autophagy increased the amount of cell death in FLCN-null cells treated with Paclitaxel, suggesting that combined treatment using Paclitaxel and an autophagy inhibitor may prove an effective treatment for BHD renal cancers. A similar combined approach using the mTOR inhibitor Rapamycin and the autophagy inhibitor Chloroquine inhibited the growth of TSC2-/- xenograft tumours and spontaneous renal tumours in TSC2+/- mice (Parkhitko et al., 2011). The Parkhitko study formed the basis of the SAIL trial, which is currently enrolling and will test the efficacy of this combined therapy for the cystic lung disease, Lymphangioleiomyomatosis (LAM). Thus it is possible that combined Paclitaxel and Chloroquine treatment could prove an effective treatment for BHD kidney cancers. Additionally, both of these drugs are already FDA-approved for other indications, meaning that they could potentially be rapidly repurposed to treat BHD.
Drugs against synthetic lethal targets are predicted to reduce the side effects often seen with traditional chemotherapy treatments as they specifically target tumour cells but not surrounding tissues. However, Paclitaxel is a chemotherapy currently used for ovarian, breast and non-small cell lung cancers, and can cause side effects such as hair loss, fatigue and increased risk from infection. Often BHD-association kidney cancers are fairly benign in their behaviour, and if found early and monitored carefully are not necessarily life-threatening (Stamatakis et al., 2013). Thus it is possible that Paclitaxel may only be an appropriate treatment for more aggressive or advanced cases of BHD, if at all.
Liu F, Liu D, Yang Y, & Zhao S (2013). Effect of autophagy inhibition on chemotherapy-induced apoptosis in A549 lung cancer cells. Oncology letters, 5 (4), 1261-1265 PMID: 23599776
Lu X, Wei W, Fenton J, Nahorski MS, Rabai E, Reiman A, Seabra L, Nagy Z, Latif F, & Maher ER (2011). Therapeutic targeting the loss of the birt-hogg-dube suppressor gene. Molecular cancer therapeutics, 10 (1), 80-9 PMID: 21220493
Parkhitko A, Myachina F, Morrison TA, Hindi KM, Auricchio N, Karbowniczek M, Wu JJ, Finkel T, Kwiatkowski DJ, Yu JJ, & Henske EP (2011). Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent. Proceedings of the National Academy of Sciences of the United States of America, 108 (30), 12455-60 PMID: 21746920
Stamatakis L, Metwalli AR, Middelton LA, & Marston Linehan W (2013). Diagnosis and management of BHD-associated kidney cancer. Familial cancer, 12 (3), 397-402 PMID: 23703644
Veldhoen RA, Banman SL, Hemmerling DR, Odsen R, Simmen T, Simmonds AJ, Underhill DA, & Goping IS (2013). The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene, 32 (6), 736-46 PMID: 22430212
Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, Merino MJ, Walther MM, Zbar B, & Linehan WM (2005). High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. Journal of the National Cancer Institute, 97 (12), 931-5 PMID: 15956655
Zhang Q, Si S, Schoen S, Chen J, Jin XB, & Wu G (2013). Suppression of autophagy enhances preferential toxicity of paclitaxel to folliculin-deficient renal cancer cells. Journal of experimental & clinical cancer research : CR, 32 (1) PMID: 24305604
www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.