How Scientists Are Overcoming Pancreatic Cancer's Drug Resistance
Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most formidable challenges in oncology. As the third leading cause of cancer-related deaths and projected to become the second within the next 15 years, this aggressive disease claims over 432,000 lives globally each year 1 .
The five-year survival rate for pancreatic cancer languishes below 10%, with most patients ultimately succumbing to the disease 2 .
c-MYC is overexpressed in 43.5% of pancreatic cancer cases, driving aggressive tumor behavior and treatment resistance 3 .
At the molecular heart of this resistance lies a fascinating and complex protein called c-MYC. This transcription factor operates as a master regulator of cellular processes, governing everything from metabolism to cell proliferation. Recent research has revealed that c-MYC doesn't work alone but interacts with critical signaling pathways, particularly the MAPK pathway, to create a resistance network that protects cancer cells from therapies 4 .
c-MYC becomes constitutively active, driving uncontrolled proliferation in pancreatic cancer.
Alters cancer cell metabolism to support rapid growth through the Warburg effect.
Enhances angiogenesis, metastasis, and immune evasion to protect cancer cells.
Under normal circumstances, c-MYC acts as a carefully controlled conductor of cellular growth, binding to specific DNA sequences and regulating genes involved in essential functions. However, in pancreatic cancer, this regulation is lost, and c-MYC becomes constitutively active, driving uncontrolled proliferation 5 .
The situation is particularly problematic because c-MYC sits downstream of KRAS, the most frequently mutated oncogene in pancreatic cancer (present in 88-95% of cases). This partnership creates a perfect storm for cancer development—mutant KRAS stabilizes c-MYC by phosphorylating it at a specific position (serine 62), increasing its stability and enhancing its ability to activate target genes 6 .
Uncovering c-MYC's Role in Drug Resistance
Researchers used conditional reprogramming (CR) to maintain cancer cells from patient samples in a state that preserved their original genetic and biological features 7 .
Treatment-naïve PDAC cells were exposed to increasing concentrations of nab-paclitaxel, creating isogenic nab-paclitaxel-resistant (n-PTX-R) cell lines.
The resistance properties were confirmed in two animal models—zebrafish and athymic nude mice.
Using techniques like immunoblotting and exome sequencing, the team analyzed differences and tested whether targeting c-MYC could restore drug sensitivity.
| Component | Purpose |
|---|---|
| Patient-derived PDAC cells | Preserve original tumor features |
| Conditional reprogramming | Enable long-term growth |
| n-PTX-R cells | Model acquired resistance |
| Zebrafish & mouse models | Validate findings in vivo |
| c-MYC depletion | Test causal relationship |
Resistance development and c-MYC expression correlation
The research yielded compelling evidence establishing c-MYC as a central driver of treatment resistance:
Targeted reduction of c-MYC restored drug sensitivity in resistant pancreatic cancer cells.
| Experimental Condition | Effect on c-MYC | Impact on Drug Sensitivity |
|---|---|---|
| c-MYC depletion in n-PTX-R cells | Decreased | Restored nab-paclitaxel sensitivity |
| c-MYC overexpression in parental cells | Increased | Reduced nab-paclitaxel sensitivity |
| MEK inhibitor (trametinib) treatment | Decreased phosphorylation | Enhanced nab-paclitaxel response |
| PP2A activator (SMAP) treatment | Increased degradation | Re-sensitized resistant cells |
Targets the MAPK pathway upstream of c-MYC, decreasing phosphorylation and stability of c-MYC.
Effectiveness in re-sensitizing cells: 75%Small molecule activator of protein phosphatase 2A (PP2A) that promotes c-MYC degradation.
Effectiveness in re-sensitizing cells: 70%Essential research tools for studying c-MYC in pancreatic cancer:
| Research Tool | Function/Application |
|---|---|
| Conditional reprogramming (CR) method | Enables long-term cultivation of patient-derived primary cells |
| c-MYC siRNA | Selectively depletes c-MYC to test functional necessity |
| pCMV-Myc-GFP plasmid | Allows controlled overexpression of c-MYC |
| MEK inhibitors (trametinib) | Blocks MAPK signaling upstream of c-MYC |
| PP2A activators (SMAP) | Promotes c-MYC degradation |
| SCH772984 (ERK inhibitor) | Specifically inhibits ERK to prevent c-MYC phosphorylation |
| Avutometinib (RAF-MEK inhibitor) | Dual RAF-MEK clamp preventing feedback activation |
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment protect cancer cells and impair c-MYC downregulation by RAF-MEK inhibitors .
FAK inhibitors (defactinib) reprogram CAFs to suppress FGF1 production, enhancing c-MYC downregulation when combined with RAF-MEK inhibitors.
Clinical Trial: NCT05669482When MEK inhibitors suppress c-MYC, this allows increased activity of MiT/TFE transcription factors that enhance lysosome biogenesis .
The resulting increase in ferritinophagy provides cancer cells with iron needed for survival under therapy stress.
Disrupting this iron supply chain represents another promising approach.
Simultaneously target p130Cas and microtubules, converging on MYC loss.
Target the transcriptional regulation of c-MYC.
Natural compound reversing gemcitabine resistance by inhibiting c-MYC and PD-L1.
The journey to understand and overcome drug resistance in pancreatic cancer has revealed c-MYC as a central player in this devastating disease. From its roles in metabolic reprogramming and angiogenesis to its recently discovered functions in iron metabolism and stromal interactions, c-MYC sits at the nexus of multiple pathways that support cancer survival under therapeutic pressure.
The experimental evidence demonstrating that c-MYC depletion can restore drug sensitivity provides a clear path forward. Rather than representing a single target, c-MYC serves as a therapeutic integration point where multiple signaling pathways converge .
This understanding has spurred the development of innovative combination therapies that simultaneously target c-MYC through different mechanisms—whether through direct degradation, transcriptional suppression, or disruption of supportive pathways like iron metabolism and stromal protection.
As research continues to unravel the complexities of c-MYC regulation, new therapeutic opportunities will emerge. The ongoing clinical trials testing combination approaches represent hope for transforming pancreatic cancer from a death sentence to a manageable disease.