Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments

Abstract

Summary Functional profiling of a cancer patient’s tumor cells holds potential to tailor personalized cancer treatment. Here, we report the utility of fresh uncultured tumor-derived EpCAM + epithelial cells (FUTCs) for ex vivo drug-response interrogation. Analysis of murine Kras mutant FUTCs demonstrates pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. By applying FUTC profiling on non-small-cell lung cancer patient samples, we report robust drug-response data in 19 of 20 cases, with cells exhibiting targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling is used to guide compassionate treatment. FUTC profiling identifies selective sensitivity to disulfiram and the combination of carboplatin plus etoposide, and the patient receives substantial clinical benefit from treatment with these agents. We conclude that FUTC profiling provides a robust, rapid, and actionable assessment of personalized cancer treatment options.

Protocol to utilize fresh uncultured human lung tumor cells for personalized functional diagnostics

“…So far, our results show that FUTCs either maintain or increase cellular viability over the course of a three day ex vivo culture period. See Figures 1 B and 3 B in our original report ( Talwelkar et al., 2021 ). The inclusion of the ROCK inhibitor Y-27632 in the F-medium used for growing FUTCs potentially helps in the survival and recovery of the primary cells.…”

“…In most cases, cell viability ex vivo is directly related to the percentage of Ki-67+ cancer cells in tumor tissue. See Figures 1 B and 3 B in our original report ( Talwelkar et al., 2021 ).…”

“…Furthermore, a KRAS mutant sample showed known combinatorial sensitivities to the MEK inhibitor trametinib and the BCL-2/BCL-xL inhibitor navitoclax. FUTC profiling was also used to guide the compassionate treatment of a lung cancer patient with an EGFR mutation (see Figure 6 in our original report) ( Talwelkar et al., 2021 ). This analysis exposed treatment responses that cannot be predicted by tumor genetic testing.…”

“…The FUTC-based approach can also be used to predict in vivo resistance to known targeted therapies. For complete details on the use and execution of this protocol, please refer to Talwelkar et al. (2021) .…”

“…For complete details on the use and execution of this protocol, please refer to Talwelkar et al. (2021) .…”