Targeting an Autocrine Loop in Small-cell Lung Cancer: Irrelevant Target or Ineffective Drug?

Bonnie S. Glisson, MD

Disclosures

Clin Lung Cancer. 2010;11(4):222 

Abstract and Introduction

Introduction

The functional autocrine loop constituted by coexpression of the KIT receptor tyrosine kinase (TK) and its ligand stem cell factor was first reported in small-cell lung cancer (SCLC) tumors and cell lines in 1991 by Hibi et al.[1] In May 2001, the notable efficacy of imatinib, a TK inhibitor (TKI), in the treatment of patients with chronic myelogenous leukemia (CML) led to its US Food and Drug Administration approval. Although the effectiveness of imatinib in CML was due to potent inhibition of the BCR-ABL fusion protein, its successful commercial development facilitated investigation of the drug's other kinase targets, KIT and platelet-derived growth factor receptor (PDGFR), in other neoplasms, including SCLC. However, in contrast to its remarkable effects in CML, gastrointestinal stromal tumors (GIST), and hypereosinophilic syndrome (HES), trials of imatinib alone,[2–4] with chemotherapy,[5,6] or as maintenance following chemotherapy, in SCLC have been uniformly negative, including the most recently reported on this issue by Schneider et al.[7] Thus, almost 2 decades after the original report, it is attempting to relegate the targeting of the SCF/KIT autocrine loop to the growing archive of failed strategies in SCLC.

In this prematurely closed phase II trial of imatinib maintenance in patients with "KIT positive" extensive SCLC, only 8 patients actually received imatinib, and although we would all agree that the results do not seem promising, the conclusions that can be made from this experience, on its own, are quite limited because of the high probability of a type II error. However, when this experience is added to the extant literature, including single-agent trials and those with synchronous chemotherapy, our judgment that imatinib is ineffective in SCLC is reinforced. Experience has shown that substantial clinical efficacy for TKIs is typically dependent upon activating mutations, chromosomal rearrangement resulting in fusion proteins, and/or gene amplification in the targeted kinases. The first 2 criteria are associated with imatinib's efficacy in CML (BCR-ABL fusion), GIST (KIT or PDGFRA mutation), and HES (FIP1L1-PDGFRA fusion). The information we have for SCLC in regard to these key characteristics is fairly limited. Mutation of KIT in exons 9 and 11 was reported in just 8% (5 of 60) of SCLC tumors in 1 series;[8] in a second series, no mutations were identified in 31 SCLC tumors in either KIT or PDGFRA.[9] In this latter series, polysomy for chromosome 4 without KIT gene amplification was observed in 19% (6 of 31) of SCLC tumors. Interestingly, these 6 cases also strongly expressed KIT protein. One could argue that a dramatic benefit for imatinib in a very small subset of patients with SCLC has not been ruled out because of patient selection, at best, for variably defined "KIT positivity" by immunohistochemistry in only some of the completed clinical trials.

But this possibility does not justify re-evaluation of imatinib to target KIT in SCLC, a disease in which advances are so desperately needed. The data in toto suggest that this autocrine loop is either irrelevant for survival and proliferation of SCLC or that imatinib does not effectively inhibit the wild-type KIT kinase. The experience with GIST that is wild type for both KIT and PDGFR is instructive here; these tumors are generally resistant to imatinib. Notably, sunitinib, a more potent inhibitor of KIT, PDGFR, and vascular endothelial growth factor receptor (VEGFR)-2, results in responses and improved survival for patients with imatinib-resistant GIST. In this regard, it is of interest that both sunitinib and cediranib, another strong inhibitor of KIT, PDGFR, and VEGFR-1-3, are in active or planned clinical trials with chemotherapy for extensive SCLC. It is not inconceivable that biomarker data from these trials may further inform us as to the potential of targeting this autocrine loop in a subset of patients.

It is clearly imperative to obtain correlative biomarker data in trials such as the ones above if we are to begin the journey toward personalized therapy for patients with SCLC.

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