PIM1 May Be a Therapeutic Target in Triple-Negative Breast Cancer

No targeted therapies are available to treat triple-negative breast cancer (TNBC). These tumors often display genomic amplification of MYC, MCL1, and the 6p21-25 genomic region that includes PIM1. Brasó-Maristany and colleagues analyzed multiple published TNBC datasets and found that PIM1 copy-number gains resulted in PIM1 overexpression in TNBCs compared with non-TNBCs. The majority of TNBC cell lines were dependent on PIM1 expression for survival and proliferation, and depletion of PIM1 induced cell death through the mitochondrial apoptotic pathway by regulating BCL2 expression. However, ectopic overexpression of the antiapoptotic BCL2 only partially rescued cell growth suggesting that PIM1 also promotes TNBC through additional mechanisms. Indeed, PIM1 depletion reduced c-MYC phosphorylation and expression of MYC target genes including MCL1, demonstrating that PIM1 activates MYC signaling. Inhibiting PIM1 with the pan-PIM kinase inhibitor AZD1208 reduced the survival of TNBC cells and suppressed tumor growth in vivo. Moreover, AZD1208 enhanced the efficacy of chemotherapy in TNBC xenografts and patient-derived xenografts (PDX) expressing high levels of PIM1. Similarly, Horiuchi and colleagues identified PIM1 as a potential druggable target in MYC-overexpressing TNBC cells via an shRNA screen. PIM1 expression was associated with expression of a MYC-dependent transcriptional signature and poor prognosis in patients with TNBC. TNBC PDXs were sensitive to the pan-PIM kinase inhibitors SGI-1776 and NVP-LGB321, which reduced tumor growth and cellular proliferation and enhanced apoptosis. However, xenografts expressing low levels of MYC were insensitive to PIM inhibition, indicating that MYC-driven TNBCs are specifically dependent on PIM kinase activity. Mechanistically, PIM1 inhibitors suppressed TNBC growth by reducing MYC transcriptional activity and increasing expression of the cyclin-dependent kinase inhibitor p27. Taken together, these studies indicate that MYC-overexpressing TNBCs are dependent on PIM1 expression and provide a rationale for clinical investigation of PIM inhibitors for the treatment of patients with TNBC.

Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, Quist J, Francesch-Domenech E, et al. PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. Nat Med 2016;22:1303–13.

Horiuchi D, Camarda R, Zhou AY, Yau C, Momcilovic O, Balakrishnan S, et al. PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat Med 2016;22:1321–9..

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