Abstract
Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients. To address this issue, we have focused on targeting the non-receptor tyrosine kinase, Src, and we and others have demonstrated that targeting Src results in inhibition of growth, invasion, and migration both in vitro and in vivo, which can be enhanced through the combined inhibition of Src and the MAPK pathway. Therefore, we examined the efficacy of the combination therapy across a panel of thyroid cancer cell lines representing common oncogenic drivers (BRAF, RAS, and PIK3CA). Interestingly, combined inhibition of Src and the MAPK pathway overcomes intrinsic dasatinib resistance in cell lines where both the MAPK and PI3K pathways are inhibited, which we show is likely due to the regulation of the PI3K pathway by Src in these responsive cells. Interestingly, we have mapped downstream phosphorylation of rpS6 as a key biomarker of response, and cells that maintain rpS6 phosphorylation likely represent drug tolerant persisters. Altogether, the combined inhibition of Src and the MAPK pathway holds great promise for improving the overall survival of advanced thyroid cancer patients with BRAF and RAS mutations, and activation of the PI3K pathway and rpS6 phosphorylation represent important biomarkers of response for patients treated with this therapy.
Highlights
Differentiated and anaplastic thyroid cancers are characteristic of poor overall survival with an average of 3.2 and 0.5 years, respectively[1]
Activation of the PI3K pathway is associated with dasatinib intrinsic resistance To identify thyroid cancer cell lines sensitive or resistant to dasatinib, we analyzed the sensitivity of 36 thyroid cancer cell lines, to the Src inhibitor dasatinib, using an IC50 cutoff of 90 nM, which is based on the peak plasma/ serum concentrations of dasatinib in patients treated for chronic myelogenous leukemia, as well as the selectivity of dasatinib (Fig. 1a)[22]
We performed Reverse Phase Protein Analysis (RPPA) to determine signaling differences between the sensitive and resistant groups, and used elastic net regression analysis to identify proteins whose expression is associated with the sensitivity and resistance to dasatinib (Fig. 1b)
Summary
Differentiated and anaplastic thyroid cancers are characteristic of poor overall survival with an average of 3.2 and 0.5 years, respectively[1] These cancers harbor a high prevalence of mutations in the MAPK pathway, in comparison to melanoma advanced thyroid cancers exhibit a reduced responsiveness to MAPK pathway inhibition[2,3,4,5,6]. Our work and the work of others have highlighted a role for the non-receptor tyrosine kinases Src Family Kinases (Src) in mediating thyroid tumorigenesis[7,8,9], and importantly we have demonstrated that prolonged inhibition of Src reprograms cells to become more reliant on the MAPK pathway[10] In support of this data, multiple laboratories have demonstrated that the combined inhibition of Src and the MAPK pathway results in synergistic inhibition of growth and increased apoptosis of thyroid cancer cells both in vitro and in vivo[10,11,12]. Having previously observed efficacy with the combined inhibition of Src and MEK1/2, in cell lines sensitive to the Src inhibitor dasatinib[10], we hypothesized that dasatinib-intrinsically
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