Biology subjects

Erickson, E.

Publications and source records attributed to Erickson, E..

3 recordsLinked to original sources

bioRxiv2022

Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation

Over 50% of human tumors display hyperactivation of the serine/threonine kinase AKT. Despite evidence of clinical efficacy, there remains scope to improve upon the therapeutic window of the current generation of AKT inhibitors. Here we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition with respect to cellular suppression of AKT-driven phenotypes in breast cancer cell lines. A systematic growth inhibition screen across 288 cancer cell lines confirmed a substantially higher potency for INY-05-040 (median GI50adj = 1.1 {micro}M) compared to our first-generation AKT degrader (INY-03-041; median GI50adj = 3.1 {micro}M), with both compounds outperforming catalytic AKT inhibition with GDC-0068 (median GI50adj > 10 {micro}M). Using multi-omic profiling and causal network integration in breast cancer cells, we demonstrate that the enhanced efficacy of INY-05-040 is associated with sustained suppression of AKT signaling, followed by a potent induction of the stress mitogen activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low baseline JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Collectively, our study presents a systematic framework for mapping the network-wide signaling effects of therapeutically relevant compounds, and identifies INY-05-040 as a potent pharmacological suppressor of AKT signaling.

cancer biology↗

bioRxiv2022

Active and passive mechanics for rough terrain traversal in centipedes

Centipedes coordinate body and limb flexion to generate propulsion. On flat solid surfaces, the limb-stepping patterns can be characterized according to the direction in which limbaggregates propagate, opposite to (retrograde) or with the direction of motion (direct). It is unknown how limb and body dynamics are modified in terrain with terradynamic complexity more representative of their natural heterogeneous environments. Here, we investigated how centipedes that use retrograde and direct limp-stepping patterns, S. polymorpha and S. sexspinosus, respectively, coordinate their body and limbs to navigate laboratory environments which present footstep challenges and terrain rugosity. We recorded the kinematics and measured the locomotive performance of these animals traversing two rough terrains with randomly distributed step heights and compared the kinematics to those on a flat frictional surface. S. polymorpha exhibited similar body and limb dynamics across all terrains and a decrease in speed with increased terrain roughness. Unexpectedly, when placed in a rough terrain, S. sexspinosus changed the limb-stepping pattern from direct to retrograde. Further, for both species, traversal of rough terrains was facilitated by hypothesized passive mechanics: upon horizontal collision of a limb with a block, the limb passively bent and later continued the stepping pattern. While centipedes have many degrees of freedom. our results suggest these animals negotiate limb-substrate interactions and navigate complex terrains, by offloading complex control and leveraging the innate flexibility of their limbs.

animal behavior and cognition↗

bioRxiv2019

Discovery of an AKT Degrader with Prolonged Inhibition ofDownstream Signaling

The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Our findings indicate that AKT degradation may confer prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.

cancer biology↗