On November 23, 2021 Mission Bio, the pioneer in high-throughput single-cell DNA and multi-omics analysis, reported a publication in Nature led by researchers from Memorial Sloan Kettering Cancer Center (MSK) that could broaden the potential benefits for KRAS G12C inhibitors like sotorasib (brand name Lumakras) in patients with lung cancer and other solid tumors (Press release, Mission Bio, NOV 23, 2021, View Source [SID1234596003]). Mission Bio’s Tapestri Platform empowered researchers to understand how resistance evolves against these lung cancer drugs by identifying secondary mutations within individual cancer cells that allowed them to bypass the therapeutic effect.

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Earlier this year, sotorasib became the first FDA-approved therapy directly inhibiting a mutation in the RAS family of oncogenes, which are implicated in a third of all cancers[1]. Sotorasib inhibits KRAS G12C in particular, which is found in 13% of patients with non-small cell lung cancers and is also common in other solid tumors like colorectal cancer. KRAS G12C inhibitors can halt disease progression for nearly 40% of patients with lung cancer carrying the mutation, but most of those who initially respond to the treatment eventually become resistant to it.

In the Nature paper titled "Diverse alterations associated with resistance to KRAS(G12C) inhibition," the team led by Dr. Piro Lito, medical oncologist at MSK, first compared patient tumor samples before and after treatment with sotorasib, identifying a host of secondary mutations that arose during treatment in genes like KRAS, NRAS, MRAS, and BRAF. But the mutations were identified using bulk next-generation sequencing (which mixes DNA from cells together), giving a limited understanding of how individual cells developed resistance.

At this point, the Tapestri Platform was used to better understand how mutations emerge in individual cells. Researchers found that the secondary mutations they identified from bulk sequencing often co-occurred with the targeted mutation (KRAS G12C) in the drug-resistant cells. These secondary mutations within the same cells were shown to circumvent the effect of target KRAS inhibitor therapy by upregulating other players in the pathway.

Dr. Jorge Reis-Filho, Director of Experimental Pathology at MSK, whose lab contributed to this work, said, "KRAS inhibitors are exciting new therapeutic agents, and understanding the basis of resistance to these new agents is essential. Tapestri and single-cell DNA sequencing can uncover important nuances of resistance mechanisms, like co-occurring mutations, which may otherwise be missed by bulk sequencing."

"Research like this is changing the landscape of cancer biology, which in turn is creating new pathways for precision cancer therapies," said Yan Zhang, CEO of Mission Bio. "Without single-cell DNA sequencing, it would have been impossible to definitively measure the co-occurrence of mutations within cancer cells and understand the mechanisms of resistance at this granular level. It’s wonderful to see Tapestri enabling the future of cancer therapeutics."

To find out how single-cell analysis can unravel the mechanisms that drive disease correction and disease progression, visit missionbio.com.