Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

Yun, Mi Ran; Lim, Sun Min; Kim, Seon‐Kyu; Choi, Hun Mi; Pyo, Kyoung‐Ho; Kim, Seong Keun; Lee, Ji Min; Lee, You Won; Choi, Jae Woo; Hong, Min Hee; Haam, Keeok; Huh, Nanhyung; Kim, Jong Hwan; Kim, Yong‐Sung; Shim, Hyo Sup; Soo, Ross A.; Shih, Jin‐Yuan; Yang, James Chih‐Hsin; Kim, Mirang; Cho, Byoung Chul

doi:10.1158/0008-5472.can-17-3146

Cited by 35 publications

(31 citation statements)

References 51 publications

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“…This study proposes a preclinical rationale that targeting YAP may be a promising strategy for the treatment of ALK-TKI-resistant NSCLC. that AXL overexpression in an EMT phenotypic context is implicated as a mechanism of resistance to ALK-TKIs (Yun et al, 2018). Consistent with these reports, in present crizotinib-resistant in vitro models with cross-resistance to other ALK-TKIs, the expression of multiple targetable candidates such as EGFR, AXL, and CYR61 was concurrently increased, and expression levels of DUSP6 and IGFBP-3 were suppressed ( Fig 2B-D and Appendix Fig S7A).…”

Section: Discussionsupporting

confidence: 87%

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK ‐rearranged lung cancer

et al. 2019

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Clinical benefit of ALK tyrosine kinase inhibitors (ALK‐TKIs) in ALK‐rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass‐molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA‐approved drugs in ALK‐TKI‐resistant models. Cerivastatin, the rate‐limiting enzyme inhibitor of the mevalonate pathway, showed anti‐cancer activity against ALK‐TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co‐regulator YAP. The marked induction of YAP‐targeted oncogenes (EGFR, AXL, CYR61, and TGFβR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient‐derived xenografts, and EML4‐ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post‐treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK‐TKIs. Our findings highlight a crucial role of YAP in ALK‐TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK‐rearranged patients with acquired resistance to ALK inhibitors.

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Section: Discussionsupporting

confidence: 87%

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK ‐rearranged lung cancer

et al. 2019

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“…Such models can be used to study processes that cannot be studied in cell lines. In this context, acquired resistance models have been established based on cell line-and patient-derived xenografts, organoids, and transgenic tumour models [115][116][117][118][119][120][121][122][123][124][125] . However, cell lines enable the establishment of a substantially larger number of models within a given timeframe and at a given cost, which is critical for studying the drug-induced heterogeneity.…”

Section: Resultsmentioning

confidence: 99%

Drug-adapted cancer cell lines as preclinical models of acquired resistance

Michaelis¹,

Wass²,

Činátl³

2019

CDR

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Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

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“…A number of studies have shown that overexpression of AXL in response to therapeutic stress can evolve through a variety of mechanisms, including transcriptional regulation (15,23,24,(50)(51)(52), post-translational regulation (53,54), and expression of miRNA (55) [reviewed in (56) Additionally, blocking AP-1 transcription activity may serve to influence the expression of key RTKs, such as EGFR (62,63), and/or to reduce the expression of the immuno-suppressor modulator of programmed cell death ligand 1 (PD-L1) (64), and hence enhance tumor elimination. The latter possibility is also supported by the findings that AXL and PD-L1 expression are correlated in different cancers (65,66), and in the cancer genome atlas (TCGA) data set for head and neck cancer (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The AP-1 complex regulates AXL expression and determines sensitivity to PI3Kα inhibition in esophagus and head and neck squamous cell carcinoma

Bdarny

Prasad

Balaban

et al. 2018

Preprint

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AXL overexpression is a common resistance mechanism to anti-cancer therapies, including the p110 isoform specific inhibitor of the phosphoinositide 3-kinase (PI3K), BYL719, in esophagus and head and neck squamous cell carcinoma (ESCC, HNSCC respectively). However, the mechanisms underlying AXL overexpression in resistance to BYL719 remained elusive. Here we demonstrated that the AP-1 transcription factors, c-JUN and c-FOS, regulates AXL overexpression in HNSCC and ESCC. AXL and c-JUN expression is correlated in HNSCC patients, and in HNSCC and ESCC cell lines. Silencing of c-JUN and c-FOS expression in tumor cells reduced AXL expression, and enhanced sensitivity of human papilloma virus positive (HPV Pos ) and negative (HPV Neg ) tumor cells to BYL719 in vitro. Blocking of the c-JUN N-terminal kinase (JNK), using SP600125, in combination with BYL719 resulted in down-regulation of AXL expression, and potently inhibited mTOR pathway. Synergistic anti-proliferative effect was detected between BYL719 and SP600125 in 15 tumor cell lines in vitro. In-vivo, this drug combination induced tumor growth arrest in cell line and patients-derived xenograft models, and in syngeneic head and neck cancer models. Collectively, our data suggests that JNK inhibition in combination with anti-PI3K therapy is a new therapeutic strategy that may be tested in HPV Pos and HPV Neg HNSCC and ESCC patients.

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Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

Cited by 35 publications

References 51 publications

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK ‐rearranged lung cancer

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK ‐rearranged lung cancer

Drug-adapted cancer cell lines as preclinical models of acquired resistance

The AP-1 complex regulates AXL expression and determines sensitivity to PI3Kα inhibition in esophagus and head and neck squamous cell carcinoma

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