RNA disruption is associated with response to multiple classes of chemotherapy drugs in tumor cell lines

Narendrula, Rashmi; Mispel-Beyer, Kyle; Guo, Baoqing; Parissenti, Amadeo M.; Pritzker, Laura B.; Pritzker, Ken; Masilamani, Twinkle; Wang, Xiaohui; Lannér, Carita

In this study, we show that RNA disruption can be induced in various cell types by structurally distinct chemotherapy agents with contrasting mechanisms of action in a dose-and time-dependent manner. The disruption fragments (at least for docetaxel) initially stem from cleavages within the expansion segments (variable regions) of the 28S rRNA. The extent of RNA disruption observed in cells reflects their sensitivity (or lack thereof) to chemotherapy drugs and cells can only tolerate a specific level of RNA disruption, above which they become nonviable. Moreover, while the induction of RNA disruption is temporally correlated with the induction of apoptosis, RNA fragmentation products accumulate over time, while apoptotic biomarkers wane. RNA disruption is associated with caspase activation and a known caspase-3 inhibitor can substantially reduce RNA disruption by docetaxel. The link between drug sensitivity in cell lines (previously assessed by clonogenic assay) and drug-induced RNA disruption strongly support our recent clinical findings that high tumor RNA disruption is associated with tumor sensitivity to drug, expressed as a pathologic complete response and enhanced disease-free survival after neoadjuvant chemotherapy in patients with locally advanced or inflammatory breast cancer [20] . RNA disruption thus appears to be a highly reproducible, natural phenomenon observed in tumor cells and represents a powerful new in vitro and in vivo biomarker of chemotherapy response.