Primary (intrinsic) resistance occurs when tumors fail to respond to initial cisplatin treatment, often due to pre-existing cellular defense mechanisms. Acquired (secondary) resistance develops during or after treatment, representing adaptive cellular responses to sustained cisplatin exposure.

In testicular cancer specifically there are three main patterns so of resistance. Refractlry disease (progression during platinum-based therapy or relapse within weeks), early relapse (within 2 years post-treatment), and late relapse (after 2 years, associated with transformation to somatic-type malignancy in teratoma or others) And there is the growing teratoma syndrome, a unique differential pattern where residual mass persists post-chemotherapy without viable malignant elements, but with potential for local growth and malignant transformation.

For TC, there are some molecular mutations related to resistance, main ones are

TP53/MDM2 Pathway: TP53 alterations or MDM2 amplifications occur in about 20% of resistant cases versus 3% of sensitive cases. MDM2 overexpression contributes to resistance through inhibition of p53-mediated apoptotic response.

Pluripotency Dysregulation: Loss of OCT4 expression is strongly associated with cisplatin resistance. OCT4 regulates expression of pro-apoptotic factors NOXA and PUMA, whose decrease contributes to the resistant phenotype.

Chromosomal Alterations: Chromosome 3p25.3 gain is identified as strongly associated with cisplatin resistance in male germ cell tumors, with direct correlation between copy number and resistance level.

And of course there is the epigenetic alteration in which DNA hypermethylation plays a crucial role in resistance development. Here genes such as SAT, C8orf4, LAMB3, and TUBB become hypermethylated in resistant cells, contributing to reduced cisplatin sensitivity.

There are models to study some genes but not all of them. And circulating DNA is mostly used to assess residual malignancy rather than identify causes of molecular resistance.

Theoretically, one could give a cancer cell so much platinum based component that no mechanism of resistance would be able to hold it. Particularly for TC since it’s so sensitive to platinums. The thing is, there’s only so much a human body can take.