Match each clinical scenario of acquired antineoplastic drug resistance with the specific foundational molecular mechanism driving the neoplastic progression.
- A 62-year-old man with metastatic colorectal cancer, initially pan-wild-type, exhibits disease progression after 8 months of panitumumab therapy.Clonal expansion of cells with a mutation in a downstream effector signaling pathway, bypassing upstream receptor blockade.
- A 55-year-old woman with metastatic non-small cell lung cancer (EGFR exon 19 deletion) progresses on erlotinib; re-biopsy identifies a new T790M mutation.Alteration of a gatekeeper residue causing steric hindrance and increased ATP affinity within the kinase domain.
- A 68-year-old woman with metastatic ER-positive breast cancer progresses on an aromatase inhibitor; circulating tumor DNA reveals an ESR1 mutation.Acquisition of a mutation in the ligand-binding domain resulting in constitutive, ligand-independent transcription factor activation.
- A 45-year-old man with chronic myeloid leukemia develops disease progression on imatinib; mutational analysis reveals a BCR-ABL1 T315I mutation.Substitution of a key residue that eliminates a critical hydrogen bond essential for targeted tyrosine kinase inhibitor binding.
Cevap
Colorectal cancer on panitumumab matches with downstream effector mutation; NSCLC T790M matches with steric hindrance and increased ATP affinity; Breast cancer ESR1 matches with ligand-independent activation; CML T315I matches with loss of a critical hydrogen bond.
The correct pairings accurately reflect the specific molecular evolutionary strategies tumors use to evade targeted therapies, distinguishing between downstream pathway activation, physical receptor alterations, and functional changes to transcription factors.
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Anahtar Kavram
Molecular Mechanisms of Acquired Antineoplastic Drug Resistance