Editors' ChoiceCancer

Untangling the diversity of KRAS-driven lung adenocarcinoma

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Science Translational Medicine  08 Jul 2015:
Vol. 7, Issue 295, pp. 295ec114
DOI: 10.1126/scitranslmed.aac8110

Vast volumes of “omic” data, including genomics, transcriptomics, epigenomics, and proteomics, have been generated for different tumor types over the past few years. A major challenge has been to translate these descriptive data into something clinically meaningful, such as prognostic indicators or therapeutic targets. As a highly prevalent cancer, lung adenocarcinoma has been subjected to multiple “omics” studies. One key finding from these efforts has been the identification of new drug targets, such as mutations in the EGFR gene, which can be treated with highly specific therapeutics. At the same time, a subgroup of lung adenocarcinoma was found to be particularly resistant to new therapeutics: lung adenocarcinoma driven by mutations in KRAS oncogene. About one-third of lung adenocarcinomas harbor activating driver mutations in KRAS, which has been notoriously difficult to target with drugs. One potential reason for this resilience is that lung adenocarcinoma is one of the most densely mutated human cancers. Thus, the repertoire of potential mutations that cooperate with KRAS is near endless.

Now, Skoulidis et al. have made a substantial contribution in bringing clarity to the diversity of KRAS-driven lung adenocarcinoma through an integrative analysis of genomic, transcriptomic, and proteomic data. Performing an unbiased analysis of transcriptomic information, the authors were able to define three robust subgroups of tumors, a finding that could be validated across data sets. Analyses of genomic information revealed that each subgroup was driven by a specific combination of mutated cancer genes, in addition to KRAS. Furthermore, the authors were able to define phenotypic and functional differences in the three tumor types, most notably differences in drug sensitivities. For example, a lung adenocarcinoma cell line belonging to one of the subgroups exhibited exquisite sensitivity to a certain drug (an HSP90 inhibitor).

The litmus test for validating these findings will be to study the classification system of KRAS-driven lung adenocarcinoma in patients, ideally in prospective trials. An important question is whether treatment responses to new KRAS inhibitors correlate with tumor subgroups. More generally, the study of Skoulidis et al. illustrates how a wealth of potential benefits to patients can be unearthed from analyses of existing big data.

F. Skoulidis et al., Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 10.1158/2159-8290.CD-14-1236 (2015). [Abstract]

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