Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma

Abstract

Mutations in Hedgehog (Hh) pathway genes, leading to constitutive activation of Smoothened (Smo), occur in medulloblastoma. Antagonists of Smo induce tumor regression in mouse models of medulloblastoma and hold great promise for treating this disease. However, acquired resistance has emerged as a challenge to targeted therapeutics and may limit their anti-cancer efficacy. Here, we describe novel mechanisms of acquired resistance to Smo antagonists in medulloblastoma. NVP-LDE225, a potent and selective Smo antagonist, inhibits Hh signaling and induces tumor regressions in allograft models of medulloblastoma that are driven by mutations of Patched (Ptch), a tumor suppressor in the Hh pathway. However, evidence of resistance was observed during the course of treatment. Molecular analysis of resistant tumors revealed distinct resistance mechanisms. Chromosomal amplification of Gli2, a downstream effector of Hh signaling, or more rarely point mutations in Smo led to reactivated Hh signaling and restored tumor growth. Unexpectedly, analysis of pathway gene-expression signatures selectively deregulated in resistant tumors identified increased phosphoinositide 3-kinase (PI3K) signaling as another potential resistance mechanism. Probing the functional relevance of increased PI3K signaling, we demonstrated that the combination of NVP-LDE225 with the PI3K class I inhibitor NVP-BKM120 or the dual PI3K/mTOR inhibitor NVP-BEZ235 markedly delayed the development of resistance. Our findings have important clinical implications for future treatment strategies in medulloblastoma.

GLI1-dependent transcriptional repression of CYLD in basal cell carcinoma

“…In addition to the regulation of EMT, the Snail family members function as regulators of proliferation or apoptosis. In this regard, suppression of Snail1, which functions as regulator of proliferation/apoptosis in different tumor types, alone or in combination with GLI may be considered as a potential anticancer approach in BCC, particularly in case of resistance to SMO inhibitors Buonamici et al, 2010) or in patients with recurrence as second line therapy. Future investigation may also clarify the function of Bcl-3 in BCC and normal skin, and address whether a combination of CYLD, Bcl-3 and Snail can be used as a detection marker for specific stages of BCC.…”

Arhgap36-dependent activation of Gli transcription factors

“…ARHGAP36-induced GLI activation may be a mechanism by which group 2 medulloblastomas acquire resistance to Smo antagonists, in addition to SMO mutations and chromosomal GLI2 amplicons (29,36,44). Furthermore, the up-regulation of ARHGAP36 in group 3 and 4 tumors alludes to a more complex relationship between GLI activity and medulloblastoma biology than has been discerned through the bulk transcriptional profiling of advanced-stage tumors.…”

“…We first analyzed previously reported microarray datasets for medulloblastoma allografts derived from Ptch1 +/− ;p53 −/− mice and propagated in the absence or presence of the Smo antagonist NVP-LDE225 (29). We found Arhgap36 to be the most up-regulated gene in NVP-LDE225-resistant medulloblastomas induced by long-term drug treatment in comparison with allografts treated briefly with the Smo inhibitor or vehicle alone (Fig.…”

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

“…(55) Recently, more than 30 inhibitors for class I PI3K have been developed for the anticancer therapy. (56) Among those, orally available, minimally toxic pan-class IA PI3K inhibitors, ZSTK474, NVP-BKM120 {5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine}, (57) NVP-BEZ235 {2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile}, (58) and GDC-0941 {2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine}, (59) have already entered clinical trials in the United States. Osteoclasts are known to be crucial for bone metastasis and cancer progression in bone.…”