Abstract
BackgroundNew therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. Autophagy can promote survival of cancer cells under stress and comprise a pathway of escape from cytotoxic therapies.MethodsWe explored the combination of ABT-737 and chloroquine, an inhibitor of autophagy, in preclinical models of SCLC. These included cell culture analyses of viability and of autophagic and apoptotic pathway induction, as well as in vivo analyses of efficacy in multiple xenograft models.ResultsCombination treatment of SCLC lines with ABT-737 and chloroquine decreased viability and increased caspase-3 activation over treatment with either single agent. ABT-737 induced several hallmarks of autophagy. However, knockdown of beclin-1, a key regulator of entry into autophagy, diminished the efficacy of ABT-737, suggesting either that the effects of chloroquine were nonspecific or that induction but not completion of autophagy is necessary for the combined effect of ABT-737 and chloroquine. ABT-737 and chloroquine in SCLC cell lines downregulated Mcl-1 and upregulated NOXA, both of which may promote apoptosis. Treatment of tumor-bearing mice demonstrated that chloroquine could enhance ABT-737-mediated tumor growth inhibition against NCI-H209 xenografts, but did not alter ABT-737 response in three primary patient-derived xenograft models.ConclusionThese data suggest that although ABT-737 can induce autophagy in SCLC, autophagic inhibition by choroquine does not markedly alter in vivo response to ABT-737 in relevant preclinical models, arguing against this as a treatment strategy for SCLC.
Highlights
New therapies are urgently needed for patients with small cell lung cancer (SCLC)
We have previously reported on a series of patient-derived xenograft (PDX) tumors, generated by direct transfer of human tumor into immunosuppressed mice, which we have used as a preclinical platform for testing novel therapeutic strategies, including ABT-737 [24,31]
Cell lines derived from LX22 and LX33 both demonstrated greater loss of viability, as determined by MTS, in response to the combination of ABT-737 and chloroquine than to either agent alone (p < 0.003 for both, see Figure 1B)
Summary
New therapies are urgently needed for patients with small cell lung cancer (SCLC). Chemotherapy and targeted therapies, including the Bcl-2 inhibitor ABT-737, may induce tumor cell autophagy. While persistent activation of autophagy may lead to tumor cell death, accumulating evidence suggests that it can serve as a protective pathway for cells to escape apoptotic cell death, allowing survival through periods of stress, growth factor withdrawal, or nutrient deprivation [8,9]. Several studies have shown that autophagy delayed apoptotic death in cancer cells undergoing chemotherapeutic treatment Treatment of these cells with inhibitors of autophagy, such as chloroquine, or knockdown of essential autophagy genes (beclin-1, ATG genes) resulted in enhanced therapy-induced apoptosis [10,11,12,13,14]. Chloroquine acts as a lysosomal pH inhibitor, preventing the fusion of autophagosomes with lysosomes and inhibiting late stages of autophagy [15,16]. These findings have led to the initiation of multiple clinical trials combining autophagy inhibitors and chemotherapeutic agents for diverse cancer types [17]
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