Editors' ChoiceCancer

Morphin’ Mutant p85α

Sci. Signal.  28 Oct 2014:
Vol. 7, Issue 349, pp. ec306
DOI: 10.1126/scisignal.aaa1565

Mutations may have diverse functional consequences (see coverage by Costa and Engelman), thereby confounding cancer therapeutic strategies based on sequencing patient tumor specimens. Several mutations in PIK3R1, encoding the p85α regulatory subunit of PI3K (phosphatidylinositol 3-kinase), induce cell proliferation by activating the PI3K pathway. In contrast, Cheung et al. found that two different mutations in PIK3R1, present in some endometrial and colon cancer cells, increased proliferation by activating a PI3K-independent pathway. The mutants encoded PIK3R1R348* and PIK3R1L370fs, both of which are truncation mutants. In a kinase inhibitor screen, expression of PIK3R1R348* increased the sensitivity of BaF3 murine myeloid cells to inhibitors targeting MAPK (mitogen-activated protein kinase) pathways, including those that inhibit MEK (a MAPK kinase) or JNK (a MAPK, c-Jun N-terminal kinase). Expression of other previously characterized PIK3R1 mutations did not alter sensitivity to MAPK inhibitors. Reverse phase protein arrays showed activation of MEK and JNK and downstream pathway substrates in BaF3 cells expressing PIK3R1R348*. Theendometrial cancer cell line OVK18, which has an allele encoding wild-type of p85α and an allele encoding PIK3R1L370fs, were sensitive to multiple MEK or JNK inhibitors in culture and in xenografts, as were several PIK3R1R348*-mutant endometrial cancer cell lines in culture. OVK18 cells exhibited phosphorylation of ERK (a MAPK, extracellular signal–regulated kinase) and JNK even when serum starved; the activation of ERK and JNK was decreased by knocking down PIK3R1L370fs, but not by either knocking down wild-type p85α or inhibiting the PI3K pathway. PIK3R1R348*-mutant endometrial cells had increased markers of the ERK and JNK pathway activity than did other endometrial tumor cells. Immunoprecipitation, gel filtration, and RNA interference showed that the BH domain of PIK3R1R348*bound the guanosine triphosphatases Cdc42 and Rac1 and acted as a scaffold for the cytosolic assembly and nuclear translocation of a JNK- signaling complex (comprising JNK, MKK7, the MAPK kinase MLK3, Cdc42, and Rac1). Introducing a nuclear export signal onto PIK3R1R348* impaired the nuclear translocation of MKK7 and MLK3 and the activation of JNK signaling. Endometrial cells stably expressing PIK3R1R348* showed increased invasive behavior in three-dimensional Matrigel cultures and increased growth in subcutaneous xenografts, both of which were suppressed by MEK or JNK inhibitors. The findings suggest that MAPK inhibitors may be a therapeutic strategy for patients with tumors with R348* or similar truncation mutations in p85α.

L. W. T. Cheung, S. Yu, D. Zhang, J. Li, P. K. S. Ng, N. Panupinthu, S. Mitra, Z. Ju, Q. Yu, H. Liang, D. H Hawke, Y. Lu, R. R. Broaddus, G. B. Mills, Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors. Cancer Cell 26, 479–494 (2014). [PubMed]

C. Costa, J. A. Engelman, The double life of p85. Cancer Cell 26, 445–447 (2014). [PubMed]

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