Drug-adapted cancer cell lines as preclinical models of acquired resistance

Acquired resistance formation limits the efficacy of anti-cancer therapies.Acquired and intrinsic resistance differ conceptually.Acquired resistance is the consequence of directed evolution,whereas intrinsic resistance depends on the(stochastic)presence of pre-existing resistance mechanisms.Preclinical model systems are needed to study acquired drug resistance because they enable:(1)in depth functional studies;(2)the investigation of non-standard treatments for a certain disease condition(which is necessary to identify small groups of responders);and(3)the comparison of multiple therapies in the same system.Hence,they complement data derived from clinical trials and clinical specimens,including liquid biopsies.Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs.Hence,we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma

Aim:Despite aggressive multiagent protocols,patients with metastatic rhabdomyosarcoma(RMS)have poor prognosis.In a recent high-risk trial(ARST0431),25% of patients failed within the first year,while on therapy and 80% had tumor progression within 24 months.However,the mechanisms for tumor resistance are essentially unknown.Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431.Methods:A Single Mouse Testing(SMT)protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine,actinomycin D,cyclophosphamide(VAC)treatment.Tumor response was determined by caliper measurement,and tumor regression and event-free survival(EFS)were used as endpoints for evaluation.Treated tumors at regrowth were transplanted into recipient mice,and the treatment was repeated until tumors progressed during the treatment period(i.e.,became resistant).At transplant,tumor tissue was stored for biochemical and omics analysis.Results:The sensitivity to VAC of 34 RMS models was determined.EFS varied from 3 weeks to>20 weeks.Tumor models were classified as having intrinsic resistance,intermediate sensitivity,or high sensitivity to VAC therapy.Resistance to VAC was developed in multiple models after 2-5 cycles of therapy;however,there were examples where sensitivity remained unchanged after 3 cycles of treatment.Conclusion:The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models.As such,it provides a platform for assessing in vivo drug resistance mechanisms at a“population”level,simulating conditions in vivo that lead to clinical resistance.These VAC-resistant models represent“high-risk”tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

New insights from the widening homogeneity perspective to target intratumor heterogeneity

Precision medicine has shed new light on the treatment of heterogeneous cancer patients.However,intratumor heterogeneity strongly constrains the clinical benefit of precision medicine.Thus,rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions,but also provide an avenue for precision medicine.Here,we explore the current approaches for targeting intratumor hetero-geneity and their limitations.Furthermore,we propose a theoretical strategy with a“homogenization”feature based on iatrogenic evolutionary selection to target intratumor heterogeneity.