Cross-resistance between ADCs

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In one sentence

Cross-resistance between ADCs occurs when the change that let a cancer survive one antibody-drug conjugate also blunts the next, most often because the two share a payload class rather than a target.

The intuition

A burglar who learns to pick one brand of lock can open every door with that lock, whatever the address. If a cancer has learned to survive the drug inside an ADC, sending the same kind of drug to a different address may meet the same defense. If the cancer instead stopped displaying the address, a new address may work. The useful question is which of those happened.

How it works

An antibody-drug conjugate (ADC) must succeed at three levels. Resistance can arise at any of them, and each predicts a different fix:

Level	What fails	Examples	What might still work
Delivery	The target protein falls, internalization slows, or the payload is not released from the lysosome	Lower target expression; loss of SLC46A3, the transporter that moves T-DM1's breakdown product (lysine-linked DM1) out of the lysosome [1]	A different target, or a design that internalizes better, such as a bispecific ADC
Payload	The released drug no longer reaches or harms its target	More efflux pumping; mutations in the payload's target enzyme	A different payload class
Cell response	The cell tolerates or repairs the damage	Stronger checkpoint signaling, better repair, a higher threshold for cell death	A drug that blocks the repair, or a payload that kills by another route

Cross-resistance follows the shared level [4]. Two ADCs aimed at different targets share the payload and response levels. Two ADCs aimed at the same target with different payloads share the delivery level; they can still share a pump that moves both payloads, or a general resistance to cell death.

Two breast cancer studies point to the payload level for today's TOP1 ADCs:

Laboratory models. Breast cancer cell lines made resistant to trastuzumab deruxtecan or sacituzumab govitecan kept their target proteins; resistance came mainly from efflux transporters. ADCs with different payload classes, including microtubule inhibitors, restored activity in cells and mice [2].
Patients. In plasma testing after progression on an ADC, 4 of 31 people with metastatic breast cancer (12.9%) had mutations in topoisomerase I, the enzyme TOP1 payloads trap; in three of the four, the mutation was undetectable before ADC treatment. The rate was 3 of 420 (0.7%) in people never treated with an ADC. Among the four patients with TOP1 mutations, median time on the first ADC was 455 days versus 52 days on the second; one patient who stopped early for side effects was excluded [3]. This is a small selected group, not a population rate.

A research reasoning map, not a treatment algorithm: in patients, these questions are rarely answered directly, and causes can coexist in different cells.

Why it matters in cancer

In metastatic triple-negative breast cancer, the approved ADCs all carry TOP1 payloads. Sorted by what each change alters: sacituzumab govitecan to datopotamab deruxtecan keeps the target (TROP2) and the payload class; a move to trastuzumab deruxtecan changes the target (to HER2) but keeps the class. Neither switch changes the payload class, so a payload-level resistance could carry over. Prospective evidence on either sequence is limited.
Trials that enroll people after a prior ADC should report which ADC and payload class they received. Without that, a response rate after "prior ADC" cannot be interpreted.
The idea organizes drug development: switching payload class (for example, to a microtubule inhibitor), engineering TOP1 payloads that evade pumps and mutations, and pairing two payloads on one antibody each target a different level.

Common confusions

A new target is not a fresh start. If the payload is the problem, a new address carrying the same drug class may fail similarly.
Shorter benefit on a second ADC does not prove cross-resistance. Later lines of therapy generally work for shorter periods; only a comparison that accounts for line of therapy can separate the two.
One mechanism does not explain every patient. Different cells in one tumor can resist in different ways.
Laboratory switching results are hypotheses for patients. Restored activity in resistant cell lines needs clinical confirmation.

How it is measured

Fresh tissue can show whether the target protein remains. Plasma or tissue sequencing can detect payload-target mutations such as TOP1 changes. In the laboratory, comparing the intact ADC, the free payload and a pump inhibitor on the same cells separates delivery failure from payload failure. None of these is yet a validated clinical test for choosing the next ADC.

In Diana's case

How this applies to her is owned by the drug-panel preferences page.

Sources and scope

Source check: November 7, 2026. Mechanism framework plus one laboratory and one clinical breast cancer study; neither establishes a sequencing rule. Expert and learner review remain pending. For the drug-development landscape, see the plain-language payload summary.

References

Kinneer et al., 2018 — SLC46A3 loss and resistance to noncleavable maytansinoid and PBD conjugates, including acquired T-DM1 resistance, in models.
Rampa et al., 2026 — payload-specific, efflux-driven resistance to trastuzumab deruxtecan and sacituzumab govitecan, reversed by payload switching in breast cancer models.
Abelman et al., 2025 — TOP1 mutations and clinical cross-resistance after ADC progression in metastatic breast cancer.
Drago, Modi and Chandarlapaty, 2021 — ADC resistance mechanisms across delivery, processing and payload.