A promising drug could be the first of an entirely new class of treatments
Photograph: Cristina Spanò
Listen to this story
AI Narrated
Your browser does not support the <audio> element.
S cientists are not usually an excitable bunch. So when many thousands of them recently gave a spontaneous standing ovation (with cheering) in the middle of a lecture, it meant something special happened. At a conference in Chicago at the end of May oncologists went wild over the results of a drug called daraxonrasib, which treats pancreatic cancer. The drug almost doubled median survival times from 6.7 months to 13.2 months. This victory over one of the most challenging cancers was an emotional moment for some.
The drug isn’t anything close to a cure. Cancers often develop resistance to targeted drugs such as daraxonrasib. The drug’s promise for patients is that, when used alongside other treatments, it might open the door to much longer survival times. Pancreatic cancers are aggressive and usually symptomless. They are usually diagnosed after they have already spread around the body. Few patients survive longer than a year, and this cancer had also turned out to be resistant to immunotherapy, a class of treatment that deploys the body’s immune system to fight tumours and which has been such a lifeline in many other cancers. The mutation in the KRAS protein, which drives most pancreatic cancers, creates an environment outside each tumour that is hostile to immune cells.
The drug is expected to speed its way through approval in America. Eventually it seems likely to be given as a first-line treatment—rather than to those who have already tried chemotherapy, as was the case in the trial. The drug works by inhibiting KRAS. Other work suggests this also changes the environment around the tumour in ways that mean the tumour may respond to immunotherapy. If this approach is successful, it could further improve survival times.
There is a bigger story. By solving the puzzle of how to inhibit signals from KRAS mutant tumours, the researchers have tackled a critical pathway that is found in many different cancers. KRAS is a molecular switch in the cell with an off and on state. A single mutation can leave the KRAS protein jammed on, endlessly signalling to cells that they should divide. Stopping KRAS in pancreatic cancer will help in other tumours where the same mutation drives the disease, such as some colorectal and lung cancers and, to a lesser degree, in endometrial, small bowel and stomach cancers.
What is more, KRAS is just one of a family of oncogenes that are collectively known as RAS mutations. Daraxonrasib could, in theory, work on other RAS -driven cancers to some degree—such as multiple myeloma. All told, RAS mutations are found in 20% of all cancers and in 3.4m cases of cancer globally every year. Little wonder that RAS has been a key target for oncologists since their discovery in 1982. But for four decades it was the white whale of oncology. Because it has a structure that some described as smooth like a golf ball there was no molecular chink with which to attack it and scientists deemed it “undruggable”. Until it wasn’t. In the end they found daraxonrasib, a small molecule that works as a “molecular glue” with another cellular protein to prevent RAS proteins from signalling.
This is just the beginning—more refined versions of the drug, and follow-on competitors, will come later. There is even hope these drugs might help an entirely different group of cancer patients: children with neuroblastoma, where a different mutation disables a gene that normally acts as a brake on RAS. Tackling one cancer has, potentially, revealed a master switch that enables new treatments for millions of people. Daraxonrasib deserves its standing ovations.■
논증 분석
유형: causal
핵심 주장
췌장암 치료제 daraxonrasib의 성공은 단순한 단일 암 치료를 넘어, 전체 암의 20%를 차지하는 RAS 돌연변이 암들에 대한 새로운 치료 패러다임을 여는 ‘마스터 스위치’를 발견한 것과 같다.
논리구조
- 전제: 췌장암은 가장 치료하기 어려운 암 중 하나로, 대부분 전이 후 진단되며 생존율이 극히 낮고 면역항암제에도 내성을 보여왔다. KRAS 단백질 돌연변이가 종양 주변 환경을 면역세포에 적대적으로 만들기 때문이다.
- 논거: daraxonrasib은 췌장암 환자의 중앙 생존 기간을 6.7개월에서 13.2개월로 거의 두 배 가까이 늘렸으며, 이는 시카고 학술대회에서 과학자들의 기립박수를 이끌어낼 만큼 획기적인 성과로 평가받았다.
- 논거: daraxonrasib은 ‘분자 접착제(molecular glue)’ 방식으로 또 다른 세포 단백질과 결합해 KRAS 단백질의 신호 전달을 차단함으로써, 40년간 ‘약물 타겟 불가(undruggable)‘로 여겨지던 KRAS를 공략하는 데 성공했다.
- 진단: KRAS는 세포 분열을 조절하는 분자 스위치로, 단 하나의 돌연변이로 켜진 상태가 고착되어 암세포가 무한히 증식하게 만든다. 이 돌연변이는 췌장암뿐 아니라 일부 대장암, 폐암, 자궁내막암, 소장암, 위암에서도 동일하게 발견된다.
- 논거: KRAS는 총칭 RAS 돌연변이로 불리는 종양유전자 계열의 일부이며, RAS 돌연변이는 전체 암의 20%, 전 세계 연간 340만 건의 암에서 발견된다. daraxonrasib은 이론적으로 다발성 골수종 등 다른 RAS 기반 암에도 효과를 보일 수 있다.
- 논거: KRAS 억제가 종양 주변 환경을 변화시켜 면역항암제에 반응하도록 만들 수 있다는 연구 결과가 있으며, 이를 병용할 경우 생존 기간이 더욱 늘어날 가능성이 있다.
- 반론: daraxonrasib은 완치제가 아니며, 표적 치료제는 암이 내성을 키우는 경우가 많다. 이 약의 실질적 가치는 단독 사용보다 다른 치료법과의 병용을 통해 더 긴 생존 가능성을 여는 데 있다.
- 처방: daraxonrasib은 미국에서 빠른 승인이 예상되며, 장기적으로는 1차 치료제로 사용될 가능성이 높고, 더 정교한 후속 약물과 경쟁 약물의 개발도 이어질 것이다. 나아가 RAS의 브레이크 역할을 하는 유전자가 비활성화된 소아 신경모세포종 환자에게도 희망을 줄 수 있다.
결론
daraxonrasib의 성공은 40년간 난공불락이었던 RAS 경로를 공략하는 데 성공함으로써, 수백만 명의 다양한 암 환자에게 새로운 치료법을 열어줄 잠재적인 암의 ‘마스터 스위치’를 발견한 것으로 평가된다.
After a free, evidence-based guide to health and wellness? Sign up to our weekly Well Informed newsletter.
Explore more
→See the latest from topics you follow
New techniques can predict and prevent lung cancer
A molecular signature can identify those most at risk
Agricultural researchers harvested wheat in the experimental fields
Too much Chinese science is ignored by the West
A bad reputation and cultural ignorance are probably responsible
illustration of a circle of robotic hands placing a puzzle piece into a matching robotic hand. The interconnected arrangement forms a continuous loop.
How artificial intelligence got better at building itself
What does “recursive self-improvement” mean for the technology?
The chemicals that reduce wrinkles
Vitamins, applied properly, can partially reverse the effects of ageing
Feeding 10 billion people will require new technology
Startups are combining AI and genetics to make more food for less money
Rocket goes boom; so do moon plans
The phenomenal explosion could blow a hole in Amazon’s plans and NASA’s too