The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D

Abstract

Levels of cyclin D increase upon AMBRA1 lossAMBRA1-knockout cells showed increased phosphorylation of RB and cell-cycle gene expression with palbociclib treatment compared to control cells (Fig. 1e, Extended Data Fig. 1p, q), which suggested an increased activity of cyclin-dependent kinases. Accordingly, we observed a notable increase of proteins in the cyclin-D family and

Insights from the degradation mechanism of cyclin D into targeted therapy of the cancer cell cycle

“…1b ). 1 , 2 , 6 , 7 Notably, AMBRA1 loss led not only to increased cyclin D levels but also promoted the formation of atypical cyclin D–CDK2 complexes. Since these active kinase complexes were insensitive to the inhibitors specific for CDK4/6, these could cause the resistant phenotype by bypassing CDK4/6 in the cell cycle.…”

“…Since these active kinase complexes were insensitive to the inhibitors specific for CDK4/6, these could cause the resistant phenotype by bypassing CDK4/6 in the cell cycle. 1 , 2 In turn, loss of CDK2 re-sensitized AMBRA1-deficient cancer cells to CDK4/6 inhibition 1 emphasizing the need for combined CDK2/4/6 inhibitors (Fig. 1b ).…”

“…In turn, does cyclin D mediate all functions of AMBRA1 in tumor suppression and CDK4/6 inhibitor resistance? The finding that cyclin D alone did not fully mimic the phenotype of AMBRA1 loss with respect to CDK4/6 inhibition may point toward additional changes beyond the mere induction of cyclin D, 2 e.g., the cyclin D–CDK2 complexes or the induction of MYC family members. 3 Lastly, the impact of AMBRA1 seems to depend on the genetic background: AMBRA1 correlates with survival in KRAS G12-mutant lung cancer, but not in KRAS wildtype or EGFR-driven lung cancer, which may reflect a more complex interplay of these pathways.…”

“…1 Chaikovsky et al searched for modulators of the response to the CDK4/6 inhibitor palbociclib and employed a genome-wide CRISPR-Cas9 screen for factors altering cellular sensitivity. 2 Maiani et al searched for the mechanism of the impact of AMBRA1 (activating molecule in beclin-1-regulated autophagy) on cell proliferation and tumorigenesis. 3…”

“…3 In development, loss of AMBRA1 was embryonically lethal with severe neural development defects from increased cell proliferation and apoptosis which could be attenuated by CDK4/6 inhibition. 1 , 3 In regard to cancer, AMBRA1 showed properties of a tumor suppressor gene as its loss promoted KRAS-driven lung adenocarcinoma 2 , 3 and lymphoma 1 growth in mice, it displayed cancer-associated mutations, 1 , 3 low expression in tumors, and its loss associated with adverse outcome. 1 , 3 Notably, cyclin D hotspot mutations in cancer abrogated AMBRA1 binding, thereby further corroborating the importance of this axis in cancer cell proliferation.…”