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When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.
Vasan, Baselga and Hyman's framework. (1) On-target: secondary mutations that block binding (EGFR T790M and C797S, ALK G1202R, BTK C481S, KRAS Y96D, ESR1 ligand-domain, AR F877L, BCR-ABL T315I) or amplification of the target (AR, BCR-ABL, MET after MET inhibition, BRAF splice variants). (2) Bypass: a parallel input restores the downstream signal (MET or HER3 amplification under EGFR blockade, RTK upregulation via loss of ERK feedback after BRAF/MEK inhibition, NRG1 fusions, IGF1R). (3) Downstream: mutation or amplification below the block (KRAS/NRAS, PIK3CA, MAP2K1, PTEN loss, CDK4/cyclin E, RB1 loss under CDK4/6 inhibition). (4) Phenotypic: lineage plasticity (neuroendocrine transformation, EMT, squamous transdifferentiation) or entry into a drug-tolerant persister state that no longer depends on the target. (5) Pharmacological/antigenic: efflux pumps, sanctuary sites (brain), drug metabolism, and for immune therapies antigen loss (CD19, BCMA, B2M) or payload-related mechanisms for ADCs (SLFN11 loss, TOP1 mutation, antigen downregulation). Pre-existing resistant subclones are selected (clonal evolution) and new mutations arise under APOBEC-driven mutagenesis. Countermeasures: next-generation inhibitors, vertical combinations (BRAF+MEK, KRAS+EGFR), parallel combinations, ctDNA-guided switching, and non-cross-resistant modalities (ADCs, radioligands, cell therapy).
Blocking a motorway. Traffic re-routes through a changed junction (target mutation), an extra lane (amplification), a parallel A-road (bypass), a road further along (downstream), a different form of transport (lineage switch), or simply avoids the roadblock's jurisdiction (efflux, sanctuary sites).
It established plasma profiling as a routine alternative to tissue for the BRCA question in advanced prostate cancer, with a sensible rule attached: if plasma finds nothing actionable, go back to tissue. It also documents at scale both the extra resistance information plasma gives and the clonal haematopoiesis noise that comes with it.
One pathway page and one bottleneck page on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It turned the laboratory prediction into a clinical rule: after a second-generation ALK inhibitor, genotype the tumour, and treat the absence of an ALK mutation as evidence that the cancer has stopped depending on ALK.
It gives the sequencing report a prognostic reading that does not depend on a repeat biopsy: an EGFR-mutant cancer that also carries RB1 and TP53 alterations will stop responding sooner and should be watched for a change of histology.
It is the practical guide to what to do after transformation: treat it as small-cell lung cancer with platinum and etoposide, expect central nervous system disease, and do not expect a checkpoint inhibitor to help.
It turned a single-centre observation into a prospectively validated one and concluded that AR-V7-positive men should be offered alternatives to abiraterone and enzalutamide. It also quantified the honest limit: two assays for the same analyte disagree on nearly one sample in five.
It changed how resistance is investigated: the first question at progression on osimertinib is whether T790M is still there, because losing it means the tumour is no longer EGFR-driven in the growing compartment and another EGFR inhibitor will not help.
It shows that the useful information in a castration-resistant plasma sample is in the repair genes and TP53 rather than in the androgen receptor finding that dominates the report, and it is the closest thing the field has to a head-to-head comparison of abiraterone against enzalutamide.
Shares BCR::ABL1 (Philadelphia chromosome), Sotorasib, Clonal evolution & minimal residual disease, ALK and the tags mechanism, mechanics-atlas.
Shares Drug efflux pumps (ABC transporters), Drug efflux pumps (ABC transporters), Lorlatinib, ALK and the tags mechanism, mechanics-atlas.
Shares ESR1 mutation, AR-V7 splice variant, Molecular determinants of resistance to antiandrogen therapy, Elacestrant and the tags mechanism, mechanics-atlas.
Shares Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas, Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes, Clonal evolution & minimal residual disease, Comprehensive genomic profiling and the tags mechanism, mechanics-atlas.
Shares PROPHECY: prospective multicentre validation of androgen receptor splice variant 7 and hormone therapy resistance in high-risk castration-resistant prostate cancer, AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer, PIK3CA / PI3K-alpha, Liquid biopsy (ctDNA) and the tags mechanism, mechanics-atlas.
Shares BTK (Bruton tyrosine kinase), BCMA, Estrogen receptor (ERα), Androgen receptor and the tags mechanism, mechanics-atlas.
Shares Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors, Circulating tumour DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer, Genomic analysis of circulating tumour DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms and the tags mechanism, mechanics-atlas.
Shares FAK (PTK2), MET, KRAS and the tags mechanism, mechanics-atlas.