Editors' ChoiceCancer

Tackling kinase inhibitor resistance

Sci. Signal.  26 Apr 2016:
Vol. 9, Issue 425, pp. ec97
DOI: 10.1126/scisignal.aaf9388

Advances in genomics have revealed driver mutations for many cancers, but exclusively targeting these drivers has limited efficacy, in part because of the emergence of nongenetic, adaptive resistance in tumors. By examining treatment-induced changes in target kinases and their signaling networks on the posttranslational level, two studies found new ways to overcome drug resistance in several types of cancer. Two common mechanisms of adaptive drug resistance are pathway rewiring and intratumoral heterogeneity. Wei et al. (see also Lam and Yaffe) combined genomic and single-cell phosphoproteomic analyses to examine the in vivo response of glioblastoma multiforme (GBM) to inhibitors of the kinase mTOR. In patient-derived glioblastoma xenografts grown in mice, neither copy number variations nor mutations revealed by whole-exome sequencing correlated with the emergence of drug resistance. However, single-cell immunohistochemical and proteomic chip analysis combined with computational analysis of excised xenografts revealed both markedly increased heterogeneity in drug-resistant tumors and activation of the kinases ERK [a mitogen-activated protein kinase (MAPK)] and SRC (a nonreceptor tyrosine kinase). Combining the mTOR inhibitor with an ERK inhibitor, a SRC inhibitor, or with both was effective at preventing tumor growth in mice bearing mTOR inhibitor–resistant GBM, whereas neither any monotherapy nor the combination of ERK and SRC inhibitors was effective. The rewiring events were detectable at the single-cell level in a small sample of cells within a few days of treatment; thus, clinicians could know very quickly on a small biopsy the cellular effectiveness of a treatment strategy.

Miller et al. found a new way in which resistance develops to inhibitors of the MAPK pathway. The proteolytic shedding of receptor tyrosine kinases (RTKs) reduces RTK signaling. In the supernatant of various cancer cell line cultures and in the plasma of mice bearing melanoma or breast cancer xenografts, treatment with a MAPK inhibitor reduced the abundance of the extracellular portions of several RTKs, including ErbB4, MET, and AXL. Consistent with decreased shedding, the MAPK inhibitor increased the abundance of the RTKs on the cell surface. In breast cancer patients that had not received MAPK inhibitor treatment, the amount of RTK extracellular portions, particularly that of AXL, circulating in their serum was increased compared with healthy controls. In melanoma patients, some that had a high amount of circulating RTKs before treatment with MAPK inhibitors had decreased amounts after treatment and this correlated positively with rapid disease progression. However, measuring the abundance of RTKs at the mRNA or protein levels in the tumors did not correlate with progression. Thus, noninvasive blood-based tests could reveal to clinicians whether a treatment is affecting RTK shedding and therefore predict the emergence of resistance before it manifests. The two studies show how understanding the changes that treatments make to signaling pathways could improve clinical strategies for monitoring and treating cancer patients.

M. A. Miller, M. J. Oudin, R. J. Sullivan, S. J. Wang, A. S. Meyer, H. Im, D. T. Frederick, J. Tadros, L. G. Griffith, H. Lee, R. Weissleder, K. T. Flaherty, F. B. Gertler, D. A. Lauffenburger, Reduced proteolytic shedding of receptor tyrosine kinases is a post-translational mechanism of kinase inhibitor resistance. Cancer Discov. 6, 382–399 (2016). [PubMed]

W. Wei, Y. S. Shin, M. Xue, T. Matsutani, K. Masui, H. Yang, S. Ikegami, Y. Gu, K. Herrmann, D. Johnson, X. Ding, K. Hwang, J. Kim, J. Zhou, Y. Su, X. Li, B. Bonetti, R. Chopra, C. D. James, W. K. Cavenee, T. F. Cloughesy, P. S. Mischel, J. R. Heath, B. Gini, Single-cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma. Cancer Cell 29, 563–573 (2016). [PubMed]

F. C. Lam, M. B. Yaffe, Kicking genomic profiling to the curb: How re-wiring the phosphoproteome can explain treatment resistance in glioma. Cancer Cell 29, 435–436 (2016). [PubMed]