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In the literature: October 2016
  1. Andres Cervantes
  1. Department of Medical Oncology, Biomedical Research Institute, Incliva, University of Valencia, Spain
  1. Correspondence to Professor Andres Cervantes; andres.cervantes{at}uv.es

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Mutational signatures with potential therapeutic interest in oesophageal adenocarcinoma

A consortium on clinical and molecular stratification on oesophageal adenocarcinoma established in Britain has recently published in Nature Genetics, a whole-genomic sequencing analysis of more than 100 samples.1 Interestingly, they describe three distinct molecular subtypes with potential treatment relevance. This observation has also been verified in an independent validation cohort. Those three types are: (1) the ones showing homologous recombination and chromosome segregation pathways defects with enrichment of a BRCA signature. These tumours would be sensitive to DNA damaging agents, including neutron and photon irradiation with the addition of PARP inhibitors, (2) a group with high mutational load and neoantigen burden, associated with an increased CD8+ T-cell density and with a dominant T>G mutational pattern, in which immunotherapy with anti-PD1 or PDL1 antibodies could have a role and (3) evidence of an ageing imprint with a C>A/T pattern and fewer unstable genomes and large duplication events, which may be sensitive to chemotherapy and antiHER2 or MET directed therapies. The clinical characteristics of the three subgroups did not differ significantly, implying that the classification, and hence spectrum of mutation patterns, does not vary with smoking, age, sex, tumour histopathological grade, tumour stage, response to chemotherapy, overall or recurrence-free survival, etc. Therefore, the mutation signature profiles seem to be capturing a different type of information compared with current clinical classification methods. Although the authors propose that these subtypes could be ascertained using a clinically applicable sequencing strategy as a basis for treatment selection, further studies will be required for preclinical validation before implementation in trials, as well as to understand the extent to which this genomic distinction is maintained downstream, at the level of the transcriptome, proteome and cellular phenotype.

Infrequent somatic mutations in lung cancer may be drivers and can induce MEK-dependent resistance to ANTI-EGFR DRUGS

Investigators at Dana Farber and Broad Institute in Harvard have reported an expression-based variant-impact phenotyping (eVIP) method to distinguish impactful from neutral somatic mutations.2 The method identified rare gain-of-function mutations in oncogenes and widespread inactivation of tumour suppressors by missense variation. eVIP was able to identify 69% of mutations analysed as impactful and 31% as functionally neutral. The application of this approach also showed that 92% of missense variants in tumour suppressor genes KEAP1 and STK11 were identified as loss-of-function variants. A subset of the impactful mutations induces xenograft tumour formation in mice and/or confers resistance to cellular epidermal growth factor receptor (EGFR) inhibition. Combining eVIP with assays for cancer phenotypes identified over a dozen rare, non-canonical mutations as gain-of-function, likely ‘driver’, oncogenic mutations. Variants of ARAF, BRAF, EGFR, ERBB2, KRAS and RIT1 are shown to be oncogenic and to induce MEK-dependent resistance to EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T and multiple BRAF variants, demonstrating that rare mutations can be functionally important in lung adenocarcinomas. The findings also support the proof of principle that high-throughput phenotyping of somatic mutations can distinguish impactful mutations from neutral mutations and generate valuable insights into patterns of functional mutations in cancer. These efforts are amenable to extension to include testing of germ-line and somatic variants and the use of genome-editing techniques to study endogenous mutations. Such future efforts might include saturating mutagenesis analysis of a small number of clinically actionable genes as well as a broad survey of mutated alleles in diverse genes. Moreover, the application of these innovative technologies for classification of mutations will begin to match the pace of genomic discovery and will accelerate the translation of genomic knowledge to clinical care. The feasibility of systematic functional interpretation of cancer genome is getting closer.

Resistance to PI3K inhibitors in breast cancer is related to PIM1 overexpression

Researchers from Memorial Sloan Kettering Cancer Center in cooperation with some other academic institutions in Boston have recently described some clinically relevant mechanisms of resistance to PI3K inhibitors.3 They used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Well-described mechanisms of resistance are MYC amplification, CDK4/6 activation, enhanced estrogen receptor function, loss of PTEN, activation of PI3Kp110β and mTOR complex activation, among others. However, a large-scale gain-of function screen for resistance to PI3K inhibition was undertaken in this work. The authors observed that two isoforms of the Proviral Insertion site in Murine leukaemia virus protein kinase family (PIM1 and PIM3) conferred robust growth in the presence of potent PI3K inhibitors. PIM kinases are highly conserved serine/threonine kinases, which are overexpressed in haematological malignancies and prostate cancer. Small-molecule PIM kinases inhibitors are currently under development, but their role in breast cancer is not defined. In a series of elegant experiments, the authors show that PIM1 overexpression was able to confer resistance to PI3K inhibitors across different context in cells lines with luminal A or B subtypes, as well as in HER2-amplified. These findings indicate that PIM1-mediated resistance may be generalisable across various breast cancer subtypes. Moreover, PIM1 overexpression does not need AKT activation to exert its blocking of PI3K inhibition. Their results support that PM1 overexpression bypasses AKT but activates PRAS40 and other downstream effectors, leading to mTOR-dependent protein translation in the presence of PI3K inhibition. Endogenous expression of PIM1 was inversely associated with sensitivity to PI3K inhibitors in PI3K-mutant breast cancer cells. On the other hand, PIM1 inhibitors are able to restore sensitivity to PI3K inhibitors in cells with overexpression of PIM1. Similar findings were confirmed in biopsies of breast tumours in patients receiving PI3K inhibitors, suggesting the clinical implication of PIM1 as an acquired mechanism of resistance to these agents. In tumour samples from previously untreated patients, 7.7% presented PMI1 copy-number gain/-amplification or mRNA overexpression. However, these tumours exhibited a mutually exclusive pattern with PI3K alterations. PIM kinases upregulation could be a clinically relevant mechanism of resistance that is therapeutically actionable. These results also suggest that the use of large-scale functional and clinical data sets paired with detailed knowledge of tumour biology may help in discovering new therapeutic avenues to circumvent resistance to anticancer-targeted agents in many cancers.

References

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Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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