Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS 1-4. Downstream of KRAS, the RAF→MEK→ERK signaling pathway plays a central role in pancreatic carcinogenesis 5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA 6. Here we show that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1→AMPK→ULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.
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MEK inhibitors and autophagy inhibitors have synergistic activity against PDAC cell lines.
“Additionally, MEK and autophagy inhibitors have synergistic activity against PDAC cell lines165.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [165]
Historically, targeting KRAS mutations has been challenging; KRAS was deemed the undruggable gene.
“Historically, targeting KRAS mutations has been challenging; it was deemed the “undruggable gene.””
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [4]
In KRAS-mutant pancreatic cancer cells, blocking the MAPK pathway reduces glucose uptake.
“In KRAS mutant pancreatic cancer cells, inhibition of the MAPK pathway downregulates glucose uptake and forces the cell to become more dependent on autophagy for survival (95, 96).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [95]
In KRAS-mutant pancreatic cancer cells, the autophagy pathway acts as a collateral dependency alongside MAPK pathway inhibition.
“Recently, through combinatorial RNAi screens and hypothesis-driven approaches, we and others have identified the autophagy pathway as a collateral dependency partner with MAPK pathway inhibitors in pancreatic cancer cells with KRAS mutation (30, 95, 96).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [95]
In KRAS-mutant pancreatic cancer cells, MAPK pathway inhibition makes the cells more reliant on autophagy to survive.
“In KRAS mutant pancreatic cancer cells, inhibition of the MAPK pathway downregulates glucose uptake and forces the cell to become more dependent on autophagy for survival (95, 96).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [95]
ERK inhibitors drive increased autophagic flux in PDAC cells to facilitate survival.
“Inhibition of the mutant KRAS-MEK-MAPK signaling cascade using ERK inhibitors drives increased autophagic flux in PDAC cells to facilitate survival224,225”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [224]
Metabolic inhibition approaches combined with RAS pathway inhibitors have shown strong preclinical data and are currently in clinical trials.
“metabolic inhibition approaches combined with RAS pathway inhibitors have shown strong pre-clinical data and are currently in clinical trials197,224,225”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [224]
Kinsey et al. initiated off-label treatment for a patient with metastatic PDAC with trametinib and hydroxychloroquine and observed a striking disease response with a 50% reduction in tumor burden without toxicity.
“Kinsey et al. initiated off-label treatment for a patient with metastatic PDAC with trametinib and hydroxychloroquine, both of which have been clinically approved for other indications. They observed a striking disease response with a 50% reduction in tumor burden without toxicity (67).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [67]
Blocking autophagy by concomitant inhibition of autophagy and MEK or ERK kinases is likely to be therapeutically beneficial in patients with KRAS-mutant pancreatic ductal adenocarcinoma, NRAS-mutant melanoma, and BRAF-mutant colorectal cancer.
“blocking this protective mechanism by concomitant inhibition of autophagy and MEK or ERK kinases is likely to be therapeutically beneficial in patients with KRAS-mutant pancreatic ductal adenocarcinoma, NRAS-mutant melanoma, and BRAF-mutant colorectal cancer (66, 67).”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [67]
Three simultaneously published studies indicated that upon inhibition of the MAPK pathway, KRAS-mutant tumors depend on autophagy for survival.
“These studies indicated that upon the inhibition of the MAPK pathway, KRAS-mutant tumors depend on autophagy for survival”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [67]
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- Authors
- Kinsey, C. G., Camolotto, S. A., Boespflug, A. M., Guillen, K. P., Foth, M., Truong, A., Schuman, S. S., Shea, J. E., Seipp, M. T., Yap, J. T., Burrell, L. D., Lum, D. H., Whisenant, J. R., Gilcrease, G. W., Cavalieri, C. C., Rehbein, K. M., Cutler, S. L., Affolter, K. E., Welm, A. L., Welm, B. E., Scaife, C. L., Snyder, E. L., & McMahon, M.
- Affiliations
- University of Utah (US)
- Huntsman Cancer Institute (US)
- Lyon 1 Université (FR)
- Corresponding author
- McMahon, Martin
- ORCID
- Venue
- Nature Medicine
- Published
- 2019-03-04
- Volume
- 25
- Issue
- 4
- Pages
- 620-627
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6452642
- OpenAlex
- W2920147611
- Cited by
- 634
- References
- 43
- Citations by year
- 2026: 32 · 2025: 59 · 2024: 78 · 2023: 78 · 2022: 104 · 2021: 133 · 2020: 106 · 2019: 41 · 2018: 1 · 2014: 1
- FWCI
- 73.24
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (F30CA235964, R01CA212415, R01CA176839, U54CA224076, R01CA131261, P30CA042014)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007491)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- pancreatic ductal adenocarcinoma, KRAS-driven cancers, MAPK/ERK pathway, MEK1/2 inhibition, trametinib, autophagy, chloroquine, hydroxychloroquine, combination therapy, therapeutic vulnerabilities
- MeSH terms
- Animals, Autophagy, Chloroquine, Humans, Pancreatic Neoplasms, Pyridones, Pyrimidinones, Mice, SCID, CA-19-9 Antigen, ras Proteins, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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