Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition

Waters, Andrew M.; Khatib, Tala O.; Papke, Bjoern; Goodwin, Craig M.; Hobbs, G. Aaron; Diehl, J. Nathaniel; Yang, Runying; Edwards, A. Cole; Walsh, Katherine H.; Sulahian, Rita; McFarland, James M.; Kapner, Kevin S.; Gilbert, Samuel F.; Stalnecker, Clint A.; Javaid, Sehrish; Barkovskaya, Anna; Grover, Kajal R.; Hibshman, Priya S.; Blake, Devon R.; Schaefer, Antje; Nowak, Katherine M.; Klomp, Jennifer E.; Hayes, Tikvah K.; Kassner, Michelle; Tang, Nanyun; Tanaseichuk, Olga; Chen, Kaisheng; Zhou, Yingyao; Kalkat, Manpreet; Herring, Laura E.; Graves, Lee M.; Penn, Linda Z.; Yin, Hongwei; Aguirre, Andrew J.; Hahn, William C.; Cox, Adrienne D.; Der, Channing J.

doi:10.1016/j.celrep.2021.109291

Cited by 19 publications

(11 citation statements)

References 92 publications

(137 reference statements)

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“…Interestingly, when investigating MAPK signalling in our cell models of NSCLC, we found that H460 βIII‐tubulin suppressed cells expressed higher basal levels of both p‐MEK and p‐ERK, suggesting a possible, as‐yet unexplored, role for βIII‐tubulin in impacting MAPK signalling. Additionally, a recent study found that βIII‐tubulin suppression decreased MYC levels, which in turn sensitised pancreatic cancer cells to ERK inhibition 46 . Whether this pathway is active in our NSCLC cells remains to be investigated.…”

Section: Discussionmentioning

confidence: 93%

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βIII‐tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c‐Met positive non‐small cell lung cancer cells

et al. 2022

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Lung cancer is one of the most common cancer types and remains a leading cause of cancer-related mortality worldwide. 1 The most common sub-type of lung cancer, non-small cell lung carcinoma (NSCLC), represents more than 80% of cases and has a dismal 5-year survival rate of less than 15%. 2 Chemotherapy remains the most effective treatment option however problems with drug resistance and toxicity present major clinical challenges. 3 Microtubules form a major component of the cell cytoskeleton and alterations in the expression of microtubule proteins are increasingly correlated with more aggressive and treatment-refractory cancers. 3 Intracellular signalling

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Section: Discussionmentioning

confidence: 93%

“…Additionally, a recent study found that βIII‐tubulin suppression decreased MYC levels, which in turn sensitised pancreatic cancer cells to ERK inhibition. 46 Whether this pathway is active in our NSCLC cells remains to be investigated.…”

Section: Discussionmentioning

confidence: 97%

βIII‐tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c‐Met positive non‐small cell lung cancer cells

et al. 2022

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“…To examine the effect of pancreas-targeted HGD of oncogenes on pancreatic tumor development, pancreatic carcinogenesis-related oncogenes of KRAS WT , KRAS G12D , 15 , 16 , 28 , 29 MYC , 30 and YAP 17 , 31 were hydrodynamically transferred to the wild-type rat pancreas, following a previously reported method, 14 which is briefly described in the materials and methods section ( Figure 1 ). The plasmids were injected either individually or in combination ( Figure 3 A).…”

Section: Resultsmentioning

confidence: 99%

Establishment of a pancreatic cancer animal model using the pancreas-targeted hydrodynamic gene delivery method

Shibata¹,

Kamimura²,

Tanaka³

et al. 2022

Molecular Therapy - Nucleic Acids

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“…Mouse studies: As previously described (78), female FVB/n mice were injected orthotopically (into the head of the pancreas) with 1,000 luciferase-expressing p53 2.1.1 syn_Luc mouse pancreatic tumor-derived cells (Kras G12D /Tp53 -/-; provided by Dr. Eric Collisson, UCSF) that had been resuspended in 50% Hanks' balanced salt solution (Gibco), 50% LDEV-free Matrigel (Corning) at a concentration of 25 cells/mL. Ketamine (80 mg/kg), xylazine (8 mg/kg), and acepromazine (1 mg/kg) were used to anesthetize the mice prior to surgery.…”

Section: Methodsmentioning

confidence: 99%

Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers

Nussbaum

Martz

Waters

et al. 2022

Preprint

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Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this novel class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.

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Targeting p130Cas- and microtubule-dependent MYC regulation sensitizes pancreatic cancer to ERK MAPK inhibition

Cited by 19 publications

References 92 publications

βIII‐tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c‐Met positive non‐small cell lung cancer cells

βIII‐tubulin suppression enhances the activity of Amuvatinib to inhibit cell proliferation in c‐Met positive non‐small cell lung cancer cells

Establishment of a pancreatic cancer animal model using the pancreas-targeted hydrodynamic gene delivery method

Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers

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