Two candidate mTOR therapy biomarkers identified in RCC

Apr 14 2014

By Sarah Pritchard, medwireNews Reporter

Two genes, TSC1 and MTOR, warrant further investigation as biomarkers for treatment benefit with rapalogs (analogs of rapamycin) in patients with renal cell carcinoma (RCC), indicate study results published in Clinical Cancer Research.

The researchers observed genomic alterations with an active effect on mTOR signalling in 11 of 14 tumour samples from five RCC patients who achieved “durable disease control” with the rapalogs temsirolimus or everolimus, which act to inhibit the mTOR complex 1 (mTORC1).

In one patient, tumour tissue analysis revealed frameshift truncation in a previously unreported somatic TSC1 single nucleotide deletion, a single copy of chromosome 9 – in which TSC1 resides – and loss of heterozygosity and a further mutation in the remaining allele, predicting “complete functional impairment of TCS1”.

“Lack of these inhibitory effects suggests hyperactivation of mTORC1 and provides a plausible explanation for sensitivity to rapalog therapy,” write James Hsieh (Memorial Sloan-Kettering Cancer Center, New York, USA) and co-authors.

Analysis of tissue from a second RCC patient also showed a novel somatic TSC1 frameshift mutation, predicted to result in the truncation of the gene product, and heterozygous loss of chromosome 9, remark Hsieh et al.

The third patient had a novel somatic missense mutation in MTOR, with the affected residue (Q2223K) localising to the phosphoinositide 3-kinase (PI3K)-related kinase domain of the MTOR protein, suggesting a functional effect. On the basis of this finding, the team introduced Q2223K mutant mTOR into human kidney cells but found it to be as sensitive to rapamycin and its analogues as wild-type mTOR. However, Q2223K mutant mTOR expression did lead to stronger phosphorylation of S6K – one of the downstream effectors of mTORC1 – than the wild-type.

Analysis of the remaining two patients' tissues did not reveal any significant alterations, note Hsieh and colleagues.

Their second study aim – to assess potential intratumour heterogeneity – found matching TSC1 mutations and heterozygous loss of chromosome 9 in all tumour regions from one patient, indicating that functional loss of TSC1 occurred early in tumour development.

In another patient, two different loss-of-function mutations in TSC1 – predicted to have an effect on sensitivity to rapalogs – emerged in two separate tumour areas. In a third patient, the researchers found evidence of “distinct genetic events involving tumor suppressors and growth-promoting genes within the same pathway [...] in spatially separate areas” of the tumour.

These findings could account for the varying treatment response sometimes seen between separate cancer metastases in the same patient, the study authors suggest.

They conclude: “[W]e provide proof of principle and identify candidate genes for future biomarker studies in this disease.”

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