Related Experiment Video

Updated: Jul 12, 2026

Automated Imaging and Analysis for the Quantification of Fluorescently Labeled Macropinosomes
11:01

Automated Imaging and Analysis for the Quantification of Fluorescently Labeled Macropinosomes

Published on: August 24, 2021

Acquisition of Resistance to RAS Inhibition Is Associated with the Upregulation of Macropinocytosis through Both

Ryan Robb1, Sarah E Ackermann1, Seamus E Degan2

  • 1Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Cancer Research Communications
|July 9, 2026
PubMed

Insights

Pancreatic cancer cells adapt to RAS inhibitors by increasing macropinocytosis, a nutrient scavenging pathway. This adaptive response, mediated by RAC1, enhances drug resistance and highlights metabolic reprogramming in KRAS-mutant pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a KRAS-addicted cancer.
  • KRAS inhibitors (RASi) show promise but face drug resistance challenges.
  • PDAC relies on macropinocytosis for nutrient scavenging to meet metabolic demands.

Purpose of the Study:

  • To investigate macropinocytosis dynamics in response to KRAS and RAS-ERK MAPK pathway inhibition.
  • To explore the role of macropinocytosis in RASi-resistant PDAC.
  • To elucidate the molecular mechanisms underlying adaptive macropinocytosis in resistant PDAC.

Main Methods:

  • Genetic suppression and pharmacological inhibition of KRAS and the RAS-ERK MAPK pathway.
  • Analysis of macropinocytosis in human PDAC cell lines and KPC-tumor derived cell lines with acquired RASi resistance.
  • Assessment of macropinocytosis-related proteins, albumin uptake, and sensitivity to albumin-bound paclitaxel.
  • Investigation of PI3K-dependent and independent pathways involving RAC1 activation.

Main Results:

  • Macropinocytosis is transiently suppressed by acute KRAS suppression but restored/enhanced by prolonged RAS pathway inhibition.
  • RASi-resistant PDAC cell lines exhibit significantly elevated macropinocytosis.
  • Resistant cells show increased macropinocytosis proteins, enhanced albumin uptake, and greater sensitivity to albumin-bound paclitaxel.
  • Adaptive macropinocytosis is mediated by PI3K-dependent/independent pathways converging on RAC1 activation.

Conclusions:

  • RASi resistance in PDAC is linked to upregulated macropinocytosis.
  • Metabolic reprogramming, specifically enhanced macropinocytosis, is a key adaptive mechanism in RASi-resistant PDAC.
  • Targeting macropinocytosis or related pathways may offer therapeutic strategies for overcoming RASi resistance in PDAC.

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...