Highlights in Cancer Research: May 2023

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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1. Blocking Genomic Instability Prevents Acquired Resistance to MAPK Inhibitor Therapy in Melanoma

Dharanipragada, P., Zhang, X. et al. Cancer Discovery. 13 (4): 880–909. (2023).
doi: 10.1158/2159-8290.CD-22-0787.

Summary of the findings

Acquired therapy resistance is mechanistically heterogeneous and, once clinically evident, liable to enhanced metastatic potential. Thus, research into specific vulnerabilities of acquired resistance must be complemented by understanding the origins of resistance (preexisting or de novo), which may rationalize preventive strategies. In this Cancer Discovery paper, the authors focused on the cancer where MAPK inhibitor (MAPKi) therapy was first developed, metastatic cutaneous melanoma, analyzed BRAFV600MUT melanoma, and extended their analysis to NRASMUT melanoma (where MAPKi-based therapy awaits development). Analysis of whole-genome sequences (WGS) delineated pervasive genomic instability, including chromothripsis. Comparative WGS analysis of patient-matched sensitive and acquired-resistant tumors revealed a specific pathway of genomic instability, gene amplification by extrachromosomal DNAs (ecDNA) and intrachromosomal complex genomic rearrangements (CGR). While ecDNAs and CGRs are present commonly in non-treated/sensitive tumors, they are distinct in acquired-resistant tumors (in their cargo genes and regulatory sequences, mutational signatures) and amplify bona fide resistance-driver genes (e.g., BRAF, NRAS, CRAF). Chromothriptic and ecDNA/CGR genomic spans overlapped non-randomly, suggesting chrommothripsis as a cause of ecDNAs/CGRs. Analysis of breakpoint-junctional sequences inferred non-homologous end-joining (NHEH) as key to ecDNA/CGR biogenesis. Targeting DNA-PKCS, a key NHEJ enzyme, prevented acquired MAPKi resistance in BRAFV600MUT and NRASMUT melanoma by limiting MAPKi-elicited ecDNA–CGR expansion.

Treatment of melanoma with MAPKi leaves persisters that later give rise to acquired resistance. Persisters may resume slowly cell cycling, with mitotic errors (e.g., lagging chromosomes, not shown) giving rise to micronuclei that enclose mis-segregated chromosomes or chromosome fragments. Micronuclei membranes are prone to rupture, exposing content chromosomes to mutagenesis and genomic instability, including chromothripsis. Genomic DNAs that drop out during re-ligation of chromothriptic fragments can circularize. Amplification of cargo genes and regulatory sequences ensue as a result of non-Mendelian inheritance of ecDNAs. Upfront DNA-PKi co-treatment attenuates ecDNA and CGR generation and prevents clonal diversification optimal for efficient escape from MAPKi.

Future impact

The immediate translational concept consists of the combination of MEKi plus DNA-PKi to treat NRASMUT melanoma, as MEKi monotherapy did not achieve clinically meaningful responses in this patient population. The same rationale may also justify clinical development for BRAFMUT or KRASMUT cancers. The notion of ecDNAs as master epigenomic reprogrammers of acquired resistance requires intense scrutiny for therapeutic opportunities. This work should spur studies to stabilize the cancer genome with the intent to prevent acquired therapy resistance. Targeting chromothripsis–ecDNA–CGR biogenesis may involve alternative pharmacologic approaches, such as mitigating chromosome segregation errors and rupture of micronuclei membranes.

Read more in Cancer Discovery