Related Experiment Video

Updated: Jun 21, 2026

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

Distinct ERK and PI3K dependencies mediate a heterogeneous response to RAS(ON) inhibition in KRAS-mutant colorectal

Philip H Choi1, Julia Meredith2, Malvika Sharma2

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Cell Reports
|June 19, 2026
PubMed

Insights

RAS inhibitors show limited efficacy in KRAS-mutant colorectal cancer (CRC). New research identifies cyclin D1 as a key factor, suggesting combination therapies targeting RAS and PI3K or MEK for improved CRC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • RAS inhibitors have shown limited success in KRAS-mutant colorectal cancer (CRC).
  • Understanding resistance mechanisms is crucial for developing effective treatments.
  • Cyclin D1 (CCND1) regulation is implicated in cancer cell proliferation.

Purpose of the Study:

  • To evaluate the efficacy of RMC-7977, a novel RAS(ON) multi-selective inhibitor, in preclinical CRC models.
  • To identify biomarkers and resistance mechanisms associated with RAS inhibitor response.
  • To inform optimal combination strategies for KRAS-mutant CRC.

Main Methods:

  • Preclinical testing of RMC-7977 in a panel of colorectal cancer models.
  • Analysis of PI3K signaling inhibition and cyclin D1 (CCND1) expression.
  • Stratification of tumors based on ERK dependence of cyclin D1 and CCND1 mRNA regulation.
  • Evaluation of combination therapies including RAS, PI3K, and MEK inhibitors.

Main Results:

  • RMC-7977 demonstrated heterogeneous responses in CRC models.
  • PI3K signaling inhibition and CCND1 expression levels correlated strongly with treatment response.
  • Two distinct resistance mechanisms were identified based on ERK dependence of CCND1.
  • Concurrent RAS and PI3K inhibition showed synergistic effects in less ERK-dependent tumors.
  • Vertical RAS and MEK inhibition was more effective in strongly ERK-dependent tumors.

Conclusions:

  • Cyclin D1 (CCND1) serves as a critical integrator of upstream signaling in KRAS-mutant CRC.
  • Stratifying tumors by ERK dependence of CCND1 can guide combination therapy selection.
  • Targeting PI3K or MEK alongside RAS inhibitors offers potential for improved efficacy in CRC.
Keywords:
CDK4/6CP: cancerKRASMEKPI3Kapoptosiscell cyclecolorectal cancercyclin D1mTOR

More Related Videos

A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells10:13

A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells

Published on: July 3, 2013

Related Concept Videos

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...
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...
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...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
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...
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...