A 58-year-old man with non-small cell lung cancer develops hypercalcemia without bone metastases. PTH-related protein (PTHrP) is elevated. Which molecular pathway underlies PTHrP production in squamous cell carcinoma of the lung?
- A Constitutive activation of PIK3CA with downstream mTORC1-driven PTHrP transcription
- B Epigenetic de-repression of PTH2 gene via EZH2 loss
- C KRAS-driven RAF/MEK/ERK signaling upregulating PTHrP promoter via AP-1 transcription factor ✓
- D Methylation-induced silencing of PTHLH inhibitors allowing constitutive PTHrP secretion
Explanation
PTHrP (encoded by PTHLH) secretion in squamous cell carcinoma of the lung is driven predominantly through RAS-MAPK pathway signaling, where mutant or amplified RAS activates RAF/MEK/ERK, which phosphorylates and activates AP-1 (Fos/Jun) transcription factors that bind the PTHrP promoter. This paraneoplastic hypercalcemia (humoral hypercalcemia of malignancy) is the classic association with squamous cell lung carcinoma. PIK3CA mutations do contribute but are not the primary mechanism for PTHrP expression; EZH2 methylates histone H3K27 and is typically a repressor whose loss de-represses genes, but PTHrP induction in this context is primarily MAPK-driven, not EZH2-dependent.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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