Editors' ChoiceCancer

Beyond molecular profiling for “precision oncology”

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Science Translational Medicine  24 Oct 2018:
Vol. 10, Issue 464, eaav3891
DOI: 10.1126/scitranslmed.aav3891

Abstract

Patient-derived tumor cultures genetically mirror patient tumors, expanding insights into therapeutic resistance.

Rapid advances in genomic profiling of tumors have profoundly expanded knowledge of tumor behavior and guided tailored chemotherapeutic regimens for patients. The result has been a societal and clinical push toward treatment guided by “personalized medicine” or “precision oncology.” Tumor behavior, however, is often guided by more than a single genetic or molecular marker. In the common setting of multiple tumor aberrations, it may therefore be difficult to predict tumor response to targeted therapeutics. Laboratory models developed to evaluate drug response each have challenges: Conventional cell lines are genetically distinct from patient tumors, and xenografts show lower tumor formation rates. Lee and colleagues attempted to split the difference, evaluating the genomic and pharmacologic landscape of 462 patient-derived tumor cells (PDCs) cultured and screened against 60 known antitumor agents within 2 to 3 weeks of biopsy.

The authors evaluated 14 tumor types and showed striking genomic similarity between PDCs and corresponding patient specimens using exome sequencing and/or single-cell RNA sequencing. PDCs revealed a long list of associations between genomic profiles of tumors and resulting drug responses. Highlighted associations include the mitogen-activated protein kinase kinase (MEK) inhibitor sensitivity with KRAS mutation, or histone deacetylase (HDAC) inhibitor resistance with RE1-silencing transcription factor expression. These analyses of genomics and drug sensitivity also helped to explain why glioma clinical trials targeting epidermal growth factor receptor (EGFR) have frequently encountered treatment resistance. The authors identified both expression of neuregulin 1 and up-regulation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-AKT-mTOR) and/or KRAS pathways to be key factors in this resistance. Treatments targeting these resistance mechanisms conferred sensitivity to EGFR inhibitors.

Perhaps most pertinent to the concept of “precision oncology,” the authors revealed that drug sensitivity in PDCs was highly predictive of the corresponding patient’s radiological response to the targeted therapeutic. Additional studies will be needed to confirm PDC findings with expanded numbers of each tumor type studied. However, the potential for PDCs to provide almost real-time prediction of effective therapeutic regimens while advancing understanding of genomic determinants of treatment response is an exciting step forward for precision medicine.

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