Abstract 4762: Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells

Namba, Kei; Shien, Kazuhiko; Takahashi, Y.; Sato, Hiroki; Yoshioka, Takahiro; Suzawa, Ken; Yamamoto, Hiromasa; Soh, Junichi; Tomida, Shuta; Toyooka, Shinichi

doi:10.1158/1538-7445.sabcs18-4762

Cited by 5 publications

(15 citation statements)

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“…Reactivation of RAS signaling via mutation and/or amplification of multiple parallel RTKs is a common mechanism driving osimertinib resistance (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), and RTK/RAS/PI3K signaling has been hypothesized as a convergent mechanism of EGFR-TKI resistance (29). We previously showed that SOS2 was critical for RTK-RAS-PI3K signaling in KRAS-mutated LUAD cells (21) and SOS2 KO reduced PI3K/AKT signaling in osimertinib-treated cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…RTK pathway reactivation represents a common mechanism driving resistance to EGFR-TKIs including osimertinib (4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), and RTK-dependent PI3K/AKT activation is a common hallmark of EGFR-TKI resistance (28,29). Using a forced HGF/MEK-driven bypass model, we found that SOS2 KO limited HGF-stimulated AKT signaling and blocked HGF-driven recalcitrance to osimertinib therapy.…”

Section: Introductionmentioning

confidence: 95%

“…Here, while the frequency and types of resistance may depend on whether osimertinib was used as first-line therapy or second-line therapy after a patient developed resistance to 1st-generation EGFR-TKIs. the most common EGFR-independent resistance mechanisms involve reactivation of the RTK/RAS/effector pathway (10), often via enhanced signaling through parallel RTKs (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). While individual RTK inhibitors may be beneficial in cancers whose resistance is driven by a specific RTK (MET, AXL, HER2/3, FGFR), broad inhibition of RTK signaling is likely required to enhance osimertinib efficacy and delay therapeutic resistance (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

Theard

Linke

Sealover

et al. 2023

Preprint

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Son of Sevenless 1 and 2 (SOS1 and SOS2) are RAS guanine nucleotide exchange factors (RasGEFs) that mediate physiologic and pathologic RTK-dependent RAS activation. Here we show that SOS2 modulates the threshold of epidermal growth factor receptor (EGFR) signaling to regulate the efficacy of and resistance to the EGFR-TKI osimertinib in lung adenocarcinoma (LUAD). SOS2 deletion sensitized EGFR-mutated cells to perturbations in EGFR signaling caused by reduced serum and/or osimertinib treatment to inhibit PI3K/AKT pathway activation, oncogenic transformation, and survival. Bypass RTK reactivation of PI3K/AKT signaling represents a common resistance mechanism to EGFR-TKIs; SOS2 KO reduced PI3K/AKT reactivation to limit osimertinib resistance. In a forced HGF/MET-driven bypass model, SOS2 KO inhibited HGF-stimulated PI3K signaling to block HGF-driven osimertinib resistance. Using a long term in situ resistance model, a majority of osimertinib resistant cultures exhibited a hybrid epithelial/mesenchymal phenotype associated with reactivated RTK/AKT signaling. In contrast, RTK/AKT-dependent osimertinib resistance was markedly reduced by SOS2 deletion; the few SOS2 KO cultures that became osimertinib resistant primarily underwent non-RTK dependent EMT. Since bypass RTK reactivation and/or tertiary EGFR mutations represent the majority of osimertinib-resistant cancers, these data suggest that targeting

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

Theard

Linke

Sealover

et al. 2023

Preprint

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“…495,496 Additionally, inhibition of AXL by the multikinase inhibitor cabozantinib reverses EMT-associated drug resistance in renal cell carcinoma and non-small-cell lung cancer. 497,498 Since 2017, the City of Hope Comprehensive Cancer Center has been conducting a phase I clinical trial of combination therapy of cabozantinib and atezolizumab, treating more than 10 different types of advanced or metastatic solid tumors (NCT03170960). Recently, their study reported that cabozantinib combined with atezolizumab showed encouraging efficacy and acceptable tolerability in advanced clear cell and nonclear cell renal cell carcinoma.…”

Section: Strategies To Inhibit Emt Inductionmentioning

confidence: 99%

“…The COX‐2 selective antagonist celecoxib was revealed to prevent EMT‐mediated malignant transformation by modulating β‐catenin nuclear localization, the vimentin/E‐cadherin proportion and EMT‐TFs (Slug, Snail and ZEB1) in colorectal cancer cells and oral squamous cell carcinoma 495,496 . Additionally, inhibition of AXL by the multikinase inhibitor cabozantinib reverses EMT‐associated drug resistance in renal cell carcinoma and non‐small‐cell lung cancer 497,498 . Since 2017, the City of Hope Comprehensive Cancer Center has been conducting a phase I clinical trial of combination therapy of cabozantinib and atezolizumab, treating more than 10 different types of advanced or metastatic solid tumors (NCT03170960).…”

Section: Emt‐based Clinical Applications In Oncologymentioning

confidence: 99%

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

Huang

Zhang

Zhou

et al. 2022

MedComm

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Epithelial–mesenchymal transition (EMT) is a program wherein epithelial cells lose their junctions and polarity while acquiring mesenchymal properties and invasive ability. Originally defined as an embryogenesis event, EMT has been recognized as a crucial process in tumor progression. During EMT, cell–cell junctions and cell–matrix attachments are disrupted, and the cytoskeleton is remodeled to enhance mobility of cells. This transition of phenotype is largely driven by a group of key transcription factors, typically Snail, Twist, and ZEB, through epigenetic repression of epithelial markers, transcriptional activation of matrix metalloproteinases, and reorganization of cytoskeleton. Mechanistically, EMT is orchestrated by multiple pathways, especially those involved in embryogenesis such as TGFβ, Wnt, Hedgehog, and Hippo, suggesting EMT as an intrinsic link between embryonic development and cancer progression. In addition, redox signaling has also emerged as critical EMT modulator. EMT confers cancer cells with increased metastatic potential and drug resistant capacity, which accounts for tumor recurrence in most clinic cases. Thus, targeting EMT can be a therapeutic option providing a chance of cure for cancer patients. Here, we introduce a brief history of EMT and summarize recent advances in understanding EMT mechanisms, as well as highlighting the therapeutic opportunities by targeting EMT in cancer treatment.

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SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status

Daley

Vieira

Rao

et al. 2022

Preprint

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KRAS is the most commonly mutated oncogene; targeted therapies have been developed against mediators of key downstream signaling pathways, predominantly components of the RAF/MEK/ERK kinase cascade. Unfortunately, single-agent efficacy of these agents is limited both by intrinsic and acquired resistance. Survival of drug-tolerant persister cells within the heterogeneous tumor population and/or acquired mutations that reactivate RTK/RAS signaling can lead to outgrowth of tumor initiating cells (TICs) and drive therapeutic resistance. Here, we show that targeting the key RTK/RAS pathway signaling intermediates SOS1 or KSR1 both enhances the efficacy of and prevents resistance to the MEK inhibitor trametinib in KRAS-mutated lung and colorectal adenocarcinoma cell lines depending on the specific mutational landscape. The SOS1 inhibitor BI-3406 enhanced the efficacy of trametinib and prevented trametinib resistance by targeting TICs, but only in KRASG12- or KRASG13-mutated LUAD and COAD cell lines that lacked PIK3CA co-mutations. Cell lines with KRASQ61 and/or PIK3CA mutations were insensitive to combination therapy with trametinib and BI-3406. In contrast, deletion of the RAF/MEK/ERK scaffold protein KSR1 prevented treatment-induced TIC upregulation and restored trametinib sensitivity across KRAS mutant cell lines in both PIK3CA-mutated and PIK3CA wildtype cancers. Our findings demonstrate that vertical targeting of RTK/RAS signaling is an effective strategy to target KRAS-mutated cancers, but the specific combination is dependent both on the specific KRAS mutant and underlying co-mutations. Thus, selection of optimal therapeutic combinations in KRAS-mutated cancers will require a detailed understanding of functional dependencies imposed by allele-specific KRAS mutations.

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Abstract 4762: Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells

Cited by 5 publications

References 0 publications

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

SOS2 regulates the threshold of mutantEGFR-dependent oncogenesis

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status

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