Small cell, big problem! Stem cells, root cause?

Small-cell lung cancer (SCLC) accounts for 13% of all lung cancer cases in the United States.1 A majority of the patients present with advanced disease. Despite impressive initial responses, death from relapsed disease is almost inevitable in extensive-stage SCLC.2 With cytotoxic chemotherapy and radiation therapy, the median survival for patients with limited-stage SCLC is only 18 months and for those with extensive stage a mere 10 months. Even more disappointingly, there have been virtually no advances in the systemic therapy of SCLC over the past 3 decades. Because the benefit from cytotoxic chemotherapy has reached a plateau in many advanced epithelial malignancies, the focus has shifted to developing drugs that target molecular changes that are essential for maintaining the malignant phenotype. The Comprehensive Review by Jahanzeb and Allen in this issue of Clinical Lung Cancer summarizes the current state of knowledge in SCLC very well. Various strategies, ingenious and otherwise, have been tested systematically over the past several years with no improvements in overall survival. What accounts for this nearly inevitable relapse and this remarkable dissonance between the initial striking response and the uniform resistance to chemotherapy upon relapse? Multiple reasons have been put forth to explain this resilience, including the expression of ATP-binding cassette (ABC) proteins that transport drugs across cellular membranes. P-glycoprotein (Pgp) and multidrug resistance protein (MRP1) are well-known ABC proteins associated with resistance to cancer chemotherapy.3 Although this issue has not been studied extensively in the clinic with regard to SCLC, there have been some striking observations. Among a group of patients with previously untreated SCLC receiving cisplatin/etoposide, the frequency of positive Pgp expression was significantly high in those with poor treatment response (stable disease or progressive disease) when compared with those with good response (complete or partial response; 60% versus 0; P < .01). The same was true for MRP1 expression as well (65% versus 0; P < .01).4 In another very small study, 4 out of 5 patients with SCLC who relapsed after receiving chemotherapy had increased expression of Pgp and MRP1.5 It is possible that the emergence of drug-resistant clones could account for poor response to treatment upon relapse. It is not clear whether this increased expression is because of the selection of a resistant clone present at the outset or upregulation of ABC proteins after exposure to chemotherapy. We do not yet have an effective agent that could overcome resistance induced by the overexpression of ABC proteins. Effective modulation of this pathway would certainly be of great interest in SCLC. Other “non pump” resistance mechanisms include mutations of genes that control cell cycle, extracellular matrix (ECM)–mediated chemotherapy resistance, Bcl-2 overexpression, and the role of stem cells. The tumor suppressor gene p53 plays a central role in regulating apoptosis, and mutations involving p53 are present in over 90% of all SCLCs.6 Mutations involving p53 might be a major mechanism by which the tumor cells circumvent apoptosis. Inactivation of retinoblastoma gene (Rb) is very common in SCLC. These two pathways that play a crucial role in the development of SCLC are notoriously difficult to target, explaining in part our difficulties in making any significant progress in the systemic therapy of SCLC beyond what is achieved with initial cytoreduction. Chemotherapy drugs, including etoposide, promote apoptosis of cancer cells by inducing DNA damage leading to the activation of caspase-3, resulting in DNA fragmentation. Small-cell lung cancer cell lines, when exposed to etoposide in the absence of ECM, resulted in DNA damage leading to caspase-3 activation and apoptosis. However, caspase-3 activation was inhibited in the presence of ECM despite DNA damage due to etoposide.7 This protective effect was reversed when the cells were exposed to an antibody against β1 integrin. Novel strategies to block the β1 integrin–mediated survival pathway should be explored in SCLC. Two major pathways are involved in apoptosis; the “extrinsic” pathway which is activated by the binding of the members of tumor necrosis factor (TNF) ligands to the death receptors (eg, CD95).8 The “intrinsic” pathway or the mitochondrial pathway is regulated by a complex interaction between the proand antiapoptotic Bcl-2 family proteins. Both of these pathways lead to the activation of proteases of the caspase family resulting in cell destruction. Overexpression of Bcl-2, which is a survival protein with anti-apoptotic effect, has been reported in SCLC and is associated with resistance to chemotherapeutic agents.9,10 Bcl-2 confers resistance to chemotherapeutic agents by inhibiting the release of editorial