Abstract
Nearly all patients with BRAF-mutant melanoma will progress on BRAF inhibitor monotherapy and combination BRAF/MEK inhibitor therapy within the first year of therapy. In the vast majority of progressing melanomas, resistance occurs via the re-activation of MAPK signalling, commonly via alterations in BRAF, NRAS and MEK1/2. A small proportion of resistant melanomas rely on the activation of the compensatory PI3K/AKT signalling cascade, although activation of this pathway does not preclude patient responses to BRAF/MEK inhibition. We now show, that PI3K/AKT signalling via potent oncogenic PIK3CA and AKT3 mutants, is not sufficient to overcome proliferative arrest induced by BRAF/MEK inhibition, but rather enables the survival of a dormant population of MAPK-inhibited melanoma cells. The evolution of resistance in these surviving tumour cells was associated with MAPK re-activation and no longer depended on the initial PI3K/AKT-activating oncogene. This dynamic form of resistance alters signalling dependence and may lead to the evolution of tumour subclones highly resistant to multiple targeted therapies.
Highlights
Introduction Acquired resistance toBRAF inhibitor monotherapy and combination BRAF/MEK inhibition occurs in most patients with metastatic BRAFV600E/K-mutant melanoma, and only 20% of patients on combination treatment remain progression free at 3 years[1]
In 50–75% of melanomas progressing on BRAF inhibitor or combination BRAF/MEK inhibition, common resistance effectors, including BRAF copy number gains, MEK1/2 and NRAS mutations promote the reactivation of MAPK signalling[2,3,4,5,6]
To explore the role of PI3K/AKT activation on cancer cell sensitivity to BRAF and MEK inhibition, we initially reviewed the association of mutations known to activate PI3K/AKT signalling, with drug sensitivity data of more than 900 cancer cell lines in the Genomics of Drug Sensitivity in Cancer (GDSC) database
Summary
Introduction Acquired resistance toBRAF inhibitor monotherapy and combination BRAF/MEK inhibition occurs in most patients with metastatic BRAFV600E/K-mutant melanoma, and only 20% of patients on combination treatment remain progression free at 3 years[1]. A further 20% of BRAF inhibitor resistant melanomas acquire alterations that stimulate both the MAPK cascade and the compensatory PI3K/AKT survival network. These alterations include gain of function NRAS and KRAS mutations and overexpression of receptor tyrosine kinases, including EGFR, PDGFRß, and MET2,5. Loss of PTEN, a negative PI3K/AKT regulator and negative prognostic factor for melanoma, is associated with shorter progression free survival in BRAF inhibitor-treated patients but is not predictive of best overall response[8,9]. Complete and partial responses to BRAF inhibition have been observed in patients with complete loss of PTEN tumour expression and with PIK3CA tumour-associated activating mutations[7,9,10]. Loss of NF1 and PTEN in melanoma cells is associated with PI3K/AKT activation, these cells
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