Curriculum
Module 07 · 70 min
RTKs, RAS-MAPK & PI3K-AKT
The two cascades that drive most solid tumors — and their targeted therapies.
CoreClinicalResearch
Topics
What this module covers
- 01RTK dimerization and trans-autophosphorylation
- 02RAS-RAF-MEK-ERK cascade
- 03PI3K-AKT-mTOR axis
- 04Targeted therapies and resistance
Deep-dive lessons
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Learning objectives
By the end of this module you will be able to
- L01Diagram the canonical EGFR → RAS → RAF → MEK → ERK cascade.
- L02Explain why BRAF V600E sensitizes melanoma to vemurafenib but produces paradoxical activation in BRAF-WT tissue.
- L03Identify common resistance mechanisms to RTK and MEK inhibitors.
Expected takeaways
What you should walk away believing
- →Constitutive activation of RAS-MAPK drives ~30% of human cancers.
- →PI3K-AKT-mTOR controls growth and survival — the most-mutated pathway in cancer.
- →Acquired resistance often goes through pathway reactivation, not target loss.
Core summary
At the Core level
Receptor tyrosine kinases like EGFR, HER2, and FGFR sit on the membrane waiting for growth factors. Once activated, they fire two parallel cascades — RAS-MAPK for proliferation, PI3K-AKT for survival — that together coordinate cell growth.
Myth vs reality
Common misconception
Claim
BRAF V600E inhibitors work in any BRAF-mutant tumor.
Reality
Colorectal BRAF V600E shows EGFR-driven feedback resistance; melanoma does not. Same mutation, different pathway context.
Evidence-graded claims
Claims, scored A–F
A
RAS-MAPK drives ~30% of cancers
Hobbs et al., 2016 review.
F
Single-agent BRAF inhibitor cures melanoma
Resistance emerges within months.
Quiz
Check your understanding
Q1. RAS is a…
Flashcards
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Front
Why combine BRAF + MEK inhibitors in melanoma?
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Pathway Atlas
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Suggested reading
Primary literature
- RAS proteins and their regulators in human disease — Simanshu, Nissley & McCormick, Cell 2017 ↗