Examkin

Question

Difficulty: Very hardNeoplastic Processes

Match each clinical scenario describing a patient with an advanced malignancy who has developed acquired resistance to a targeted antineoplastic therapy with the most likely underlying molecular mechanism of resistance.

  • A 62-year-old woman with metastatic non-small cell lung cancer harboring an EGFR exon 19 deletion progresses with new brain metastases after 18 months of initial therapy with osimertinib.Emergence of a C797S point mutation preventing covalent drug binding, or bypass track activation via MET amplification.
  • A 45-year-old man with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase develops progressive leukocytosis and early blast crisis after 2 years on imatinib.Acquisition of a T315I gatekeeper missense mutation that sterically hinders targeted inhibitor binding within the active site.
  • A 59-year-old man with metastatic BRAF V600E-mutated cutaneous melanoma develops new hepatic metastases after initially achieving a dramatic response to vemurafenib monotherapy.Reactivation of the downstream MAPK signaling cascade via secondary NRAS mutations or amplification of the primary kinase target.
  • A 70-year-old man with metastatic castration-resistant prostate cancer develops worsening bone pain and a rapidly rising PSA level after 10 months of treatment with abiraterone acetate.Expression of a truncated steroid receptor splice variant that lacks the C-terminal ligand-binding domain but remains constitutively active.

Answer

NSCLC/osimertinib resistance matches with C797S mutation or MET amplification. CML/imatinib resistance matches with the T315I gatekeeper mutation. Melanoma/vemurafenib resistance matches with MAPK reactivation via NRAS mutation or target amplification. Prostate cancer/abiraterone resistance matches with truncated steroid receptor splice variants.
Each class of targeted therapy exerts specific selective pressure on tumor cells, leading to predictable molecular mechanisms of resistance. Recognizing these patterns is essential for sequencing next-line therapies. Osimertinib resistance occurs via C797S or bypass tracks. Imatinib resistance is driven by the T315I gatekeeper mutation. Vemurafenib resistance involves paradoxical MAPK pathway reactivation. Abiraterone resistance involves androgen receptor modifications like AR-V7.

Step-by-Step Solution

1
Analyze the non-small cell lung cancer scenario on osimertinib.
Matches with C797S mutation or MET amplification.
Osimertinib relies on covalent binding to mutated EGFR; the C797S mutation directly disrupts this binding. Alternatively, the tumor bypasses EGFR completely via MET amplification.
2
Analyze the chronic myeloid leukemia scenario on imatinib.
Matches with the T315I gatekeeper missense mutation.
T315I is the classic structural alteration in the ABL kinase domain that blocks imatinib binding, necessitating salvage therapy with ponatinib or asciminib.
3
Analyze the melanoma scenario on vemurafenib.
Matches with reactivation of the downstream MAPK signaling cascade.
Melanoma cells overcome isolated BRAF inhibition by upregulating alternative pathway components (like NRAS), driving ERK signaling independent of the inhibited BRAF.
4
Analyze the prostate cancer scenario on abiraterone acetate.
Matches with expression of a truncated steroid receptor splice variant.
Abiraterone works by systemic androgen depletion; the tumor adapts by expressing an androgen receptor variant (AR-V7) that activates transcription even in the absence of androgen ligands.

Key Concept

Molecular mechanisms of acquired resistance to targeted antineoplastic therapies
Rate this question

Topics

Neoplastic Processes

More questions from this topic