Targeted Therapy and Signal Transduction
Targeted therapies inhibit specific oncogenic signaling pathways including RAS-MAPK, PI3K-AKT-mTOR, and others that drive cancer cell survival.
## Overview
Signal transduction cascades relay growth factor signals from the cell surface to the nucleus, regulating gene expression, cell cycle progression, and survival. In cancer, these pathways are constitutively activated by mutations or amplifications, making their components attractive drug targets for precision oncology.
## RAS-MAPK Pathway
RAS (KRAS, NRAS, HRAS) activates RAF→MEK→ERK kinase cascade, driving proliferation. BRAF V600E mutation activates MAPK constitutively and is present in ~50% of melanomas, ~10% of CRC.
**BRAF V600E inhibitors**: Vemurafenib, dabrafenib. Highly effective in melanoma (initial ORR ~50%) but resistance develops rapidly via paradoxical MAPK reactivation. Combination with MEK inhibitors (trametinib, cobimetinib) delays resistance and improves survival. Skin toxicity (cutaneous SCC, keratoacanthoma) occurs frequently.
**KRAS G12C inhibitor**: Sotorasib and adagrasib covalently bind KRAS G12C in its inactive (GDP-bound) conformation, preventing RAS activation. Approved for NSCLC with KRAS G12C mutation.
## PI3K-AKT-mTOR Pathway
PI3K phosphorylates PIP2→PIP3, recruiting AKT, which activates mTOR among other targets. PTEN (phosphatase) normally degrades PIP3; PTEN loss activates PI3K pathway. PIK3CA mutations occur in ~30% of breast cancers.
**mTOR inhibitors**: Everolimus and temsirolimus are rapalogs (mTORC1 inhibitors) used in RCC, PNET, and HR+ breast cancer. **PI3K inhibitors**: Alpelisib targets PIK3CA mutations; approved for PIK3CA-mutant HR+/HER2- breast cancer with fulvestrant. Requires PIK3CA mutation testing. Major toxicity: hyperglycemia (manage with metformin).
**AKT inhibitors**: Capivasertib (AKT1/2/3 inhibitor) recently approved in combination with fulvestrant for AKT1/PIK3CA/PTEN-altered HR+/HER2- breast cancer.
## Other Targeted Pathways
**FGFR inhibitors** (erdafitinib, infigratinib): FGFR2/3 fusions and mutations in urothelial and intrahepatic cholangiocarcinoma. **RET inhibitors** (selpercatinib, pralsetinib): RET fusions in NSCLC and thyroid cancer. **MET inhibitors** (capmatinib, tepotinib): MET exon 14 skipping mutations in NSCLC. **NTRK inhibitors** (larotrectinib, entrectinib): TRK fusions — tumor-agnostic approval.
## Key Takeaways
- BRAF V600E inhibitors + MEK inhibitors provide superior outcomes vs. monotherapy in melanoma
- KRAS G12C (sotorasib/adagrasib) targets a previously undruggable oncogene via covalent inactive-state binding
- PI3K-mTOR pathway drugs require biomarker testing (PIK3CA mutation, PTEN status)
- NTRK and RET inhibitors have tumor-agnostic approvals based on molecular alteration regardless of histology