Patient-derived models of acquired resistance can identify effective drug combinations for cancer

Abstract

Targeted cancer therapies have produced substantial clinical responses but most tumors develop resistance to these drugs. Here we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with EGFR or ALK tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MEK inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and FGFR inhibitors was active in an EGFR mutant resistant cancer with a novel mutation in FGFR3. Combined ALK and SRC inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.

Expansion of airway basal epithelial cells from primary human non‐small cell lung cancer tumors

“…Studies that report normal epithelial cell expansion have tended to initiate culture from early‐stage primary NSCLC tumors, whereas studies in which cancer cells have been expanded have initiated culture using biopsies or effusions from patients with late‐stage, therapy‐resistant disease7, 8, 9 or from PDX models,24 which may be more aggressive and/or more adaptable to cell culture. This would be consistent with traditional NSCLC cell culture methods and PDX models, where patient models are more readily established from late‐stage, metastatic or therapy‐resistant disease than from early‐stage primary disease.…”

“…Protocol differences exist between the aforementioned studies: key studies have used inactivated human dermal fibroblasts7, 8 as feeder layers rather than the mouse embryonic fibroblasts often used in those that see normal cell expansion and it has also been possible to transition tumor cell cultures off feeder layers after 6 months of culture establishment 8. We have previously demonstrated that adult human lung fibroblasts do not support long‐term normal airway epithelial cell expansion in the same way as 3T3‐J2 cells17 so the use of adult and/or human feeder cells might favor tumor cell expansion.…”

“…In non‐small cell lung cancer (NSCLC), a number of reports demonstrate successful primary tumor cell culture using fibroblast co‐culture and ROCK inhibition 7, 8, 9, 10. However, others have found that normal epithelial cells are preferentially expanded in these conditions 11, 12.…”

Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma

“…Src regulates many fundamental cellular processes, including cell growth, differentiation, migration, and drug resistance (22,(29)(30)(31)(32). In our study, acquisition of acquired resistance to dovitinib is attributable to the activation of a Src-driven bypass signaling pathway.…”

“…Previous studies have demonstrated that Src sits on the signaling node mediating resistance to multiple anticancer agents (22). The increased activation of Src led us to hypothesize that Src activation directly mediated acquired resistance to dovitinib in LC-2/ad DR cells.…”