Tumor heterogeneity underlies differential cisplatin sensitivity in mouse models of small cell lung cancer

SCLC is the most aggressive subtype of lung cancer characterized by a remarkable response to chemotherapy followed by development of resistance. Mechanisms of initial sensitivity and of subsequent resistance are not understood. Here we highlight a broad tumor heterogeneity in mouse models of SCLC, which includes a CDH1 high primary cisplatin-resistant peripheral neuroendocrine lesion with unique metabolic and structural profile. Cisplatin treatment preferentially eliminates CDH1 negative secondary tumor leaving behind CDH1 high primary lesions, thus revealing a striking differential response. We profile global protein and messenger RNA levels in vehicle and cisplatin treated lung tumor populations and find a marked reduction in proliferation and a pronounced metabolic shift following cisplatin-treatment. Our proteo-transcriptomic analysis gives insight into gene expression alterations that characterize cisplatin resistance and uncovers potential novel targets to overcome resistance of distinct populations. SCLC tumors in the mouse show heterogeneity which appears, as might be the case in humans, to be one of the underlying mechanisms of differential sensitivity to cisplatin.