Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer

Shah, Khyati N.; Bhatt, Roma; Rotow, Julia; Rohrberg, Julia; Olivas, Victor; Wang, Victoria E.; Hemmati, Golzar; Martins, Maristela Santini; Maynard, Ashley; Kuhn, Jonathan; Galeas, Jacqueline; Donnella, Hayley; Kaushik, Sushmita; Ku, Angel A.; Dumont, Sophie; Krings, Gregor; Haringsma, Henry J.; Robillard, Liliane; Simmons, Andrew; Harding, Thomas C.; McCormick, Frank; Goga, Andrei; Blakely, Collin M.; Bivona, Trever G.; Bandyopadhyay, Sourav

doi:10.1038/s41591-018-0264-7

Cited by 204 publications

(155 citation statements)

References 42 publications

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“…We cannot exclude that ubiquitination of TPX2 would be enough to abrogate interaction, or that loss of interaction would be an indirect consequence of APC/C-CDC20 activity. However, our idea is consistent with the early degradation of TPX2 that we observe, and studies indicating TPX2 as a major substrate for APC/C at mitotic exit [51,52] and numerous observations that amplification of TPX2 is the ratelimiting event for increased AURKA activity associated with tumorigenesis [48,53]. One interesting conclusion to be drawn from our model is that although AURKA destruction during mitotic exit is a FZR1-dependent event, AURKA inactivation during mitotic exit is dependent on CDC20, along with all of the other known critical events of mitotic exit.…”

Section: Discussionsupporting

confidence: 91%

AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

Abdelbaki

Akman

Poteau³

et al. 2019

Preprint

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Activity of AURKA is controlled through multiple mechanisms including phosphorylation, ubiquitinmediated degradation, and allosteric interaction with TPX2. Activity peaks at mitosis before AURKA is degraded during mitotic exit in a process strictly dependent on APC/C coactivator FZR1. We used FZR1 knockout cells (FZR1 KO ) and a novel FRET-based AURKA biosensor to investigate how activity is regulated in absence of destruction. We found that AURKA activity in FZR1 KO cells dropped at mitotic exit as rapidly as in parental cells, despite absence of destruction. Unexpectedly, TPX2 was degraded normally in FZR1 KO cells. Overexpression of an N-terminal TPX2 fragment sufficient for AURKA binding, but not degraded at mitotic exit, caused delay in AURKA inactivation. We conclude that AURKA inactivation in mitotic exit is determined not by its own degradation but by degradation of TPX2 and therefore dependent on CDC20 rather than FZR1. The biosensor revealed that FZR1 instead suppresses AURKA activity in interphase and is critically required for assembly of the interphase mitochondrial network after mitosis.

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Section: Discussionsupporting

confidence: 91%

AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

Abdelbaki

Akman

Poteau³

et al. 2019

Preprint

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“…In this study, the IC50 of osimertinib was 7.593 μM, which was higher than that of the H1975OR osimertinib-resistant cells (0.8-2.5 μM) established by other laboratories, 29 which might be related to our H1975OR-resistant cell line after a longer time of drug resistance screening. The establishment of our drug-resistant cell line took about 22 weeks, while other studies report that it took about 6-12 weeks.…”

Section: Discussioncontrasting

confidence: 60%

“…A series of studies have been published on acquired resistance to osimertinib. [24][25][26][27][28][29][30] The L858R mutation combined with T790M mutation was found to be more similar in real-world patients who acquired T790M mutation after firstor second-generation TKIs. 10,11 In this study, common osimertinib resistance mechanisms, such as C797X, loss of T790M, amplification of MET, and the mutation of KRAS, BRAF, MEK and PI3K, were not found in H1975OR cells, 23,30 which is similar to previous studies 13 and represents a more common clinical situation.…”

Section: Discussionmentioning

confidence: 88%

“…25,29 Shah et al found that for H1975, osimertinib and rociletinib were used to induce drug resistance, respectively, and secondary TPX2 overactivation caused the increase of AURKA phosphorylation and BIM phosphorylation, which led to BIM ubiquitin degradation unable to play its role in inducing apoptosis. 25,29 AURKA inhibitor MLN8237 could block the phosphorylation of BIM, and BIM could induce apoptosis again to reverse the drug resistance of TKI of the third-generation osimertinib. Aurora kinase inhibitors were found to suppress this adaptive survival program, thereby increasing the magnitude and duration of EGFR inhibitor response in preclinical models.…”

Section: Discussionmentioning

confidence: 99%

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CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)

Qin

Liang

et al. 2020

Thoracic Cancer

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Background The third‐generation EGFR‐TKI, represented by osimertinib, has been widely used in clinical practice; however, resistance eventually emerges. At present, it remains unclear whether an abnormal cell cycle is involved in acquired resistance, and whether the combination of palbociclib (CDK4/6 inhibitor) and osimertinib can overcome the third‐generation TKI resistance. Methods We established osimertinib‐resistant cells (H1975 OR) derived from EGFR‐mutant NSCLC cells H1975. Drug effects on cells were assessed with Cell Counting Kit‐8 (CCK8). Protein alterations were detected with western blot analysis. RT‐PCR was used to evaluate the differences of gene mRNA. Cell cycle distribution of H1975 S and H1975 OR cells was compared using flow cytometry. Results Compared with H1975, the sensitivity of H1975OR to the CDK4/6 inhibitor was increased and the proportion of cells in G1 phase was decreased. The mRNA level of CDK4, CDK 6 and the protein level of CDK4, pRB were increased in H1975OR. In the H1975OR cells, palbociclib significantly increased the proportion of G1 phase cells. The combination of osimertinib and palbociclib synergistically decreased the survival of H1975OR by cell cycle arrest. Combined treatment was found to inhibit the initial phosphorylation of RB by inhibiting the function of CDK4/6, significantly reducing the level of p‐RB, and blocking cell proliferation. Conclusions An osimertinib acquired resistance cell line (H1975 OR) was successfully established. The expression of cell cycle related genes was altered in H1975OR. The expression of CDK4 and the phosphorylation of Rb, the downstream molecule of CDK4/6, was increased in H1975OR cells. The combination of CDK4/6 inhibitor palbociclib and osimertinib could overcome the acquired resistance of osimertinib.

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“…The understanding that non-mutational mechanisms may play a role in tumor relapse has prompted multiple studies focused on identifying factors that contribute to overall persister fitness (Shaffer et al, 2017;Shah et al, 2019;Viswanathan et al, 2017). However, since most persisters remain arrested during drug treatment (Sharma et al, 2010), factors that contribute to persister-driven relapse are hard to discern by bulk profiling.…”

mentioning

confidence: 99%

Cycling cancer persister cells arise from lineages with distinct transcriptional and metabolic programs

Oren

Tsabar

Cabanos

et al. 2020

Preprint

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Non-genetic mechanisms have recently emerged as important drivers of therapy failure in cancer (Salgia and Kulkarni, 2018), where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment (Vallette et al., 2019). While most cancer persisters, like their bacterial counterparts, remain arrested in the presence of drug, a rare subset of cancer persisters can re-enter the cell cycle under constitutive drug treatment (Sharma et al., 2010). Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drug. Here, using time-lapse imaging, we found that cycling persisters emerge early in the course of treatment of EGFR-mutant lung cancer cells with the EGFR inhibitor osimertinib. To study this rare, transiently-resistant, proliferative persister population we developed Watermelon, a new high-complexity expressed barcode lentiviral library for simultaneous tracing each cell's clonal origin, proliferative state, and transcriptional state. Analysis of Watermelon-transduced PC9 cells demonstrated that cycling and non-cyclingpersisters arise from different pre-existing cell lineages with distinct transcriptional and metabolic programs. The proliferative capacity of persisters is associated with an upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation in specific subpopulations of tumor cells. Mitigating oxidative stress or blocking metabolic reprograming significantly alters the fraction of cycling persister cells. In human tumors, programs associated with cycling persisters were induced in malignant cells in response to multiple tyrosine kinase inhibitors. The Watermelon system enabled the identification of rare persister lineages, that are preferentially poised through specific gene programs to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.Angie Martinez Gakidis for scientific editing.

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Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer

Cited by 204 publications

References 42 publications

AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

AURKA destruction is decoupled from its activity at mitotic exit but suppresses interphase activity

CDK4/6 inhibitor palbociclib overcomes acquired resistance to third‐generation EGFR inhibitor osimertinib in non‐small cell lung cancer (NSCLC)

Cycling cancer persister cells arise from lineages with distinct transcriptional and metabolic programs

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